Renal‐hepatic‐pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity

Abstract

Background

Renal‐hepatic‐pancreatic dysplasia type 2 (RHPD2) is a rare condition that has been described in the literature disproportionately in perinatal losses. The main features of liver and kidney involvement are well described, with cardiac malformations and cardiomyopathy adding additional variation to the phenotype. Many patients reported are within larger cohorts of congenital anomalies of kidney and urinary tract (CAKUT) or liver failure, and with minimal phenotypic and clinical course data.

Methods

An independent series of phenotypes and prognosis was aggregated from the literature. In this literature review, we describe an additional patient with RHPD2, provide a clinical update on the oldest known living patient, and report the cumulative phenotypes from the existing published patients.

Results

With now examining the 17 known patients in the literature, 13 died within the perinatal period‐pregnancy to one year of life. Of the four cases living past the first year of life, one case died at 5 years secondary to renal failure, the other at 30 months secondary to liver and kidney failure. Two are currently alive and well at one year and 13 years. Two cases have had transplantation with one resulting in long‐term survival.

Conclusions

These patients serve to expand the existing phenotype of RHPD2 as a perinatal lethal condition into a pediatric disorder with variable expressivity. Additionally, we introduce the consideration of transplantation and outcomes within this cohort and future patients.

Renal‐Hepatic‐Pancreatic Dysplasia type 2 (RHPD2) is a rare condition that has been described in the literature disproportionately in perinatal losses. The main features of liver and kidney involvement are well described but the longevity and treatment of patients leaves many questions. We present a literature review with updated information on existing cases to summarize outcomes and better define RHPD2.

1. INTRODUCTION

Multiple congenital anomalies in fetuses are being detected increasingly well with ultrasound technology (Boyd et al., 2012). Up to two thirds of birth defects can be detected antenatally, and Talati et al. found up to one fifth of those birth defects can be congenital anomalies of the kidney and urinary tract (CAKUT). With increasing prenatal diagnosis of anomalies, comes larger uptake of genetic testing in the perinatal period. Exome sequencing studies in these populations have revealed multiple fetuses with variants in NEK8 (OMIM # 609799). NEK8 has been seen to cause a ciliopathy, renal‐hepatic‐pancreatic dysplasia type 2 (RHPD2). This condition is highly variable in the phenotypes reported in the literature. There is a consistency in the hepatic, renal, and cardiac anomalies noted; but inconsistency in outcomes and lethality. To date, there are 16 patients reported in the literature with RHPD2 and this paper serves to summarize these cases, describe an additional case, and define the existing phenotype and potential expressivity (Talati et al., 2019).

2. MATERIALS AND METHODS

2.1. Editorial policies and ethical considerations

The study was approved by an ethics committee and was exempt from IRB approval based on the format of the research. Our patient and the patient reported in Vasilescu et al. gave informed consent to have de‐identified information reported in this study.

2.2. Literature review

A literature review was conducted to identify other patients reported with RHPD2 for additional phenotypic information. The literature search was conducted on February 10th, 2022, via PubMed using the search terms: NEK8 and Renal‐hepatic‐pancreatic dysplasia type 2. The resulting matches were reviewed. We collected the phenotypic characteristics of 16 additional patients presented in the literature, including updated phenotypic information on an existing patient in the literature. Descriptive statistics are used to summarize the data. Due to the small group sizes, comparisons were not performed.

2.3. Inclusion and exclusion criteria

The subjects for this study were identified by querying public journals and databases. Included subjects were reported between January 2013 and October 2020. They were included based on homozygous or compound heterozygous NEK8 variants and a phenotype consistent with RHPD2. Those with a diagnosis of Nephronophthisis type 9 were excluded. A retrospective chart review was performed documenting demographics, family and prenatal history, clinical diagnoses, radiologic studies, and operative procedures.

2.4. Genetic testing methods

RHPD2 was diagnosed by a variety of genetic testing methodologies within multiple institutions. Testing methodologies include targeted gene sequencing, custom exon enriched gene panels, homozygosity mapping with genome data of homozygous regions, next generation sequencing with Sanger sequencing confirmation and whole exome and genome sequencing. Testing was completed on a combination of blood and amniotic fluid, depending on the patient. The NEK8 gene had the same assembly reference throughout the literature, GRCh38.p14 (GCF_000001405.40). The reference sequence for all patients was NM_178170.3. No additional reference or version was considered within the study.

3. RESULTS

3.1. Demographics

In total, the literature review identified 16 patients with RHPD2, diagnosed by genetic testing and clinical phenotype, and we report one additional patient. These patients demonstrated no sex predominance, although there were fetal demises without a documented sex. Ethnicities were underreported in the cohort, but six had a listed ethnicity, and these represented multiple ethnic groups. Approximately 4 out of 6 patients were Caucasian, with either Finnish or Dutch ancestry; one patient was Saudi Arabian, and one other was Chinese. Consanguinity was endorsed in 7 families, but 6 children had RHPD2 with compound heterozygous variants and no reported consanguinity. Based on reports in the literature, the median life expectancy if a patient was deceased before term was 26 weeks; which includes 7 of the patients in the cohort that either miscarried or those terminated for severe anomalies. The interquartile range was 21–26 weeks, concentrated mostly in the second trimester. The median life expectancy of those that survived after delivery was 85 days, which is approximately 2.5 months, which included the 6 patients reported before our case, and excluded the known living patient. The interquartile range was 15 days to 30 months.

The RHPD2 patients in the literature were identified to have 18 unique variants, including missense, nonsense, splice, and frameshift. These variants comprised 12 families representing 16 individuals with RHPD2, with the inclusion of our case there were 20 novel variants amongst 13 families and 17 patients. All variants were unique to each kindred. Ninety‐percent of variants were identified in one of the two functional domains of NEK8 (Figure 1).

FIGURE 1.

NEK8, its domains, and its variants. NEK8 consists of 15 coding exons (black and white boxes) with only a single known transcript. It belongs to the regulator of chromosome condensation 1 (RRC1) superfamily. This superfamily is defined by the presence of RCC1‐like domains (RLDs), 7 homologous domains, which form a seven‐bladed β‐propeller. Canonical RCC1 repeats are defined through UniProt(dark blue boxes); however, sequence alignments across the RCC1 superfamily allow for identification of 7 total repeats of similar sequence and length providing non‐canonical RCC1 repeats (light blue boxes) (Hadjebi et al., 2008). There is also a serine/threonine kinase domain (Uniprot, 2021) (dark red boxes). Variants for all patients are provided and numbered: missense—blue, splice—red, nonsense—purple. 8 of 20 variants were identified in the kinase domain, 10 of 20 variants in an RCC1 repeat, 1 variant lies between RCC1 domains, and 1 variant occurs at the terminus of the gene and results in frameshift read through of the canonical stop codon. The tables summarize the numbered variant providing codon and protein variants as reported by original publications and domains in which these variants were identified. Figure is to scale and adopted from Grampa et al. using the UCSC genome browser (Kent et al., 2002) and reference sequence NM_178170.3.

3.2. Review of the literature

Otto et al. first reported patients with pathogenic variants in NEK8, describing a cohort affected with Nephronophthisis type 9 (NPHP9). The authors identified three variants that disrupted conserved sites and were typed as highly likely to be homozygous. A subsequent mouse model showed that Nek8 was the cause of multinucleated cells in the ciliary tubule and that with a mutant Nek8 there is an inability to nucleate the cilium. Nek8 was determined to be crucial for proper cilia signaling and homozygous changes in NEK8 were predicted to cause a ciliopathy in humans. Subsequently, Grampa et al. found that knockout of the Nek8 gene, with missense mutations, in zebrafish embryos resulted in a classic ciliopathy‐related phenotype consistent with NPHP9. However, they also found that loss‐of‐function mutations led to a proliferative phenotype that best resembled a multiple congenital anomaly syndrome. They did several functional studies including: ciliogenesis, proliferation, apoptosis and epithelial morphogenesis—ultimately demonstrating the stark difference between NEK8 mutations with a loss‐of‐function capacity and missense mutations. This is the basis of the mechanism allowing NEK8 to cause two allelic ciliopathies—homozygous or compound heterozygous gain‐of‐function mutations causing NPHP9; and loss‐of‐function mutations causing a unique, congenital anomaly syndrome RHPD2 (Otto et al., 2008).

Frank et al. described the first family with multiple fetuses having RHPD2 (Table 1). That paper elaborated on a consanguineous family with three fetuses showing cystic dysplasia of the liver and kidney with cardiac anomalies, concerning for a ciliary defect. NEK8 was implicated in linkage studies. Given the concern in multiple systems the name renal‐hepatic‐pancreatic dysplasia type 2 was the given diagnosis.

TABLE 1.

This chart is modified off of Hassan et al., 2020 to include all documented cases of renal‐hepatic‐pancreatic dysplasia type 2

Study	N	Outcome	Liver findings	Cardiac findings	Renal findings	Additional findings	Variants
Frank et al. (2013)	3	Termination at 21 weeks	Cystic dysplasia	NA	Enlarged cystic dysplastic kidneys	Uterine agenesis, bowed femur diaphysis, hypoplastic lungs	Hom c. 1795 C>T One consanguineous family
		Miscarriage at 18 weeks	Severe autolysis	Truncus arteriosus and unseptated atrium/ventricle	Absent lobulation	Asplenia, lung lobulation defect, HT, shortened legs
		Termination at 22 weeks	Cystic dysplasia	Truncus arteriosus and unseptated atrium/ventricle	Enlarged cystic dysplastic kidneys	Talipes equinovarus, bowed femur diaphysis
Rajagopalan et al. (2015)	2	Death at 4 months	HB; hepatocellular vacuolization; cholestasis	Severe HCM; AS/PS	Polycystic kidneys, enlarged	Ileal obstruction; respiratory insufficiency	CH c. 1043C>T; c.2096_2070insC in both children
		Death at 15 days	Canalicular cholestasis, hepatocyte vacuolization	PS; L‐TGA; biventricular hypertrophy	Enlarged and hyperechogenic	NA
Al‐Hamed et al. (2016)	1	Stillborn	NA	NA	Cystic kidneys; oligohydramnios	Dilated cisterna magna; bilateral bowed femurs	Hom c.1401 G > A
Grampa et al. (2016)	5	Fetal death—26 weeks	Cystic biliary fibro‐adenomatosis; ductal plate anomalies	NA	Bilateral renal cysts and enlargement; luminal calcification fibrosis	Facial dysmorphism, arthrogryposis; enlarged cystic pancreas	Hom: c.47+1G>A
		Fetal death—28 weeks	NA	NA	Bilateral enlarged kidneys with cystic dysplasia and fibrosis	Enlarged and cystic pancreas; absent uterus and vagina; agenesis of posterior vermis	CH: c.618G>A c.1246G>A
		Fetal death—26 weeks	BDP	Cardiomegaly with intraventricular communication	L kidney agenesis and R with hypodysplasia and fibrosis	Asplenia, narrow thorax, bowed femurs	CH: c.379C>T c.1384C>T
		Death at 3 days	BDP	HCM; intraventricular septum hyperplasia	R microcysts; L Major hypodysplasia and macrocysts	Facial dysmorphisms; ACC; narrow thorax; bowed femurs	Hom c.1783G > A
		Death at 50 days	Hepatomegaly and cholestasis; BDP and fibrosis	Cardiomegaly; PDA; intraventricular septum hyperplasia	R major hypodysplasia; L nephropathy with dysplasia and cortical fibrosis	NA	CH c.1804c>T c.259A>G
Lei et al. (2017)	1	Termination at 26 weeks	NA	TGA	Bilateral dysplasia; oligohydramnios	NA	Hom c.1418‐1G>A
Vasilescu et al. (2018)	1	Alive at 13 years	Congenital cholestasis; liver cirrhosis	Hypertrophic cardiomyopathy; LVFO	NA	Liver transplant at 2 years; delayed growth, short stature	CH c.644T>C; c.1055G>T
Liu et al. (2020)	1	Termination in pregnancy	NA	LSVC; large coronary sinus; VSD; R aortic arch; pulmonary atresia	NA	HT; asplenia; intestinal malrotation; multiple regions of AOH	Hom c.689A>T
Hassan et al. (2020)	2	Death at 5 years	Direct HB; cholestasis; BDP; mild bridging fibrosis; ESLD	AS/PS, pulmonic stenosis; LA dilation; cardiac failure	2 small kidneys; dialysis at age 3; ESRD	Hepatopulmonary syndrome; liver transplant at 21 months	Hom c. 35G>T Same in both siblings
		Death at 30 months	Direct HB; cholestasis; BDP; ESLD; portal HTN	AS/PS; bradycardiac arrest; LV hypertrophy; cardiac failure	Small L kidney; ESRD	Severe malnutrition; ascites
Our Study	1	Alive at current age	Calcifications, direct HB and cholestasis (resolved)	Aortic valve stenosis; Ventricular hypertrophy	L renal agenesis; R hydronephrosis	Cloacal abnormality; hemivertebra; imperforate anus; non‐immune hydrops	CH c. 37G>A; c. 1148G>C

Note: All variants mentioned are in reference to NM_178170.3 of the NEK8 gene.

Abbreviations: ACC, agenesis of the corpus callosum; AS/PS Aortic/pulmonic valve stenosis; BDP, Bile duct paucity; CH, compound heterozygous; HB, hyperbilirubinemia; HCM, hypertrophic cardiomyopathy; Hom, homozygous; HT, heterotaxy; HTN, hypertension; L, left; NA, none mentioned in article; R, right; TGA—transposition great arteries.

The first living children to be given the diagnosis of RHPD2 were from Rajagopalan et al., which described 2 siblings with compound heterozygous pathogenic variants in NEK8. Each had a cardiac defect and echogenic kidneys. One died from complications of hypertrophic cardiomyopathy, and the other with canalicular cholestasis. These brothers showed intrafamilial variability but also demonstrated viability contrary to the fetal deaths reported to date. Al‐Hamed et al., Lei et al., and Liu et al. all presented cases of stillbirths, terminations, or pregnancy loss with confirmed RHPD2. The largest cohort to date was defined by Grampa et al. with three fetal demises and two patients that lived into their first month. Focusing on NEK8's role in the Hippo pathway the authors were able to describe variable expressivity in their cohort as many of the same anomalies were seen but with substantially different life expectancy.

Hassan et al. is the most recent study to describe RHPD2 patients surviving into childhood. These children had chronic kidney disease progressing to end‐stage renal disease. These patients were the first in the literature to survive the perinatal period and also suggest the concept of transplantation within RHPD2 patients. One child had a deceased donor liver transplant after developing end‐stage liver disease with hepatopulmonary syndrome. Despite correction of this child's liver disease and hepatopulmonary syndrome, he developed progressive renal and valvular heart disease, which culminated in cardiac arrest and a need for peritoneal dialysis, with death by age 5 years. His sibling was not offered organ transplantation but developed end‐stage liver and renal disease, portal hypertension and malnutrition. He died at 30 months after suffering bradycardic arrest. These cases clearly highlight the potential to live into childhood and longevity with transplantation, but also the progressive nature of this disease despite transplantation.

A patient that had not been discussed within the existing case series was described by Vasilescu et al. This patient was reported in a larger series of cardiomyopathy patients in Finland who received exome sequencing. She was reported to have compound heterozygous variants in NEK8, and first appeared to care with neonatal cholestasis. Her condition progressed, and at age 3 had a histological analysis of native liver that showed decreased number of intrahepatic biliary ducts, cholestasis, and severe cirrhosis—prompting a liver transplant. This was consistent with a diagnosis of RHPD2, and she is likely the oldest reported patient as she was 10 years at the time of publication. Contacting her team years after the report, revealed she is currently still alive at 13 years and monitored for cardiac complications. She was diagnosed with hypertrophic obstructive cardiomyopathy (HOCM) after liver transplantation. She had significant left ventricular outflow tract obstruction, peak gradient >90 mmHg, noted one year after transplantation that improved significantly following conversion of tacrolimus to cyclosporine, peak gradient decreased <50 mmHg. The family moved abroad, where she was exposed to growth hormone therapy (GH) and significant worsening in HOCM was observed. After discontinuation of GH, there was improvement of HOCM. Currently, the heart muscle is mildly hypertrophied (+3 SD, with <50 mmHg peak gradient), but without significant impact on her daily living. Glomerular filtration rate before liver transplant was 81 ml/min, and latest in 2021, 69 ml/min, which is within normal limits for liver transplant patients and ultrasonography of the kidney parenchyma looks normal. Her liver function has been excellent after transplantation with the exception of one episode of mild acute cellular rejection one year after transplant, treated successfully. Aside from short stature, height Z = −3.63, her development is typical for age.

3.3. Clinical report

Our patient was the second pregnancy for a 35 year old Caucasian and Japanese mother. Prenatal care was routine until 18 weeks gestation when the fetus was seen to have multiple anomalies including: polyhydramnios, fetal non‐immune hydrops, absent left kidney, cystic right kidney and hepatomegaly. She was born at 29 weeks via vaginal delivery after premature rupture of membranes. Her birth weight was 1.7 kg, which was greater than the 97th percentile for her gestation. She was edematous on exam, with features consistent with hydrops fetalis. Her postnatal imaging confirmed the prenatal anomalies, but also identified a hemivertebra, imperforate anus, cloacal anomaly and hypoplastic aortic valve with ventricular hypertrophy. She required surfactant, nitric oxide, and the oscillator for respiratory distress syndrome, pulmonary hypertension, and possible pulmonary hypoplasia. She was eventually weaned to room air. The bilateral cardiac ventricular hypertrophy noted at birth was followed with serial echocardiograms and no longer appreciated at discharge.

She had multiple genitourinary defects and required surgery for her cloacal abnormality including vaginostomy and cystostomy with concurrent tube placement. Initial renal ultrasound showed left renal agenesis and right kidney with hydroureteronephrosis. The urinary tract dilatation was attributed to obstruction due to cloacal anomaly and voiding cystourethrogram showed no vesicoureteral reflux. Although she experienced multiple episodes of acute kidney injury due to obstructive processes, eventually her glomerular filtration rate normalized for age.

On a gastroenterological basis, she was born with an imperforate anus that required a diverting colostomy with mucous fistula. She had an exploratory laparotomy to resect a walled off segment with primary anastomosis. She was noted to have a direct bilirubin on day 1 of life of 0.4 mg/dl. Over the first three months of life, she developed cholestatic liver disease with elevated GGT, which worsened significantly following an episode of Staphylococcal non‐aureus bacteremia diagnosed at 2 months of age. Serial ultrasound at 1 and 2 months of age revealed multiple hepatic calcifications and a poorly visualized and then contracted gallbladder. A HIDA scan at 2½ months did reveal excretion of radiotracer in the bowel thereby excluding biliary atresia, but the poor uptake and excretion of the tracer was suggestive of severe hepatitis. An MRCP obtained shortly thereafter was suggestive of an atretic gallbladder but no biliary dilation. The patient was started on ursodiol 30 mg/kg/day around 2 months of age and after successful treatment of bacteremia, the cholestasis eventually resolved 3 months of age. On long‐term follow‐up she remained on ursodiol, at a reduced dose of 15 mg/kg/day, with completely normal LFTs and GGT by 11 months of age. Follow‐up ultrasound at 11 months revealed 2 small hepatic calcifications and a baseline ultrasound elastography of the liver was consistent with some F2‐F3 fibrosis. Platelet count and INR were normal and not suggestive of severe liver disease or hepatic dysfunction. On discharge exam, she presented with large left sided inguinal hernia. Pediatric surgery was notified and found it likely to be a protruding ovary.

After discharge home from the neonatal intensive care unit at 3 ½ months of age, 45 weeks post conceptual age, she was readmitted to our intensive care unit for respiratory distress due to RSV bronchiolitis. Long‐term sequelae of RSV infection in prematurity was felt to exacerbate her existing bronchopulmonary disease due to prematurity. Readmission for respiratory distress then occurred 3 weeks later and was attributed to silent aspiration. Nasogastric feedings were begun to limit potential feeding aspiration and since gastrostomy tube placement could not be undertaken at the time due to her anatomy.

In follow‐up, our patient was seen at one year by our team, corrected age 9 months. She had multiple orthopedic problems and was in a spica cast for right hip dislocation. This casting did not correct hip placement and was going to be removed. She had scoliosis being closely monitored. She failed Auditory Brainstem Response exams and had seen Audiology for tube placement as well as hearing aid placement for a conductive hearing loss. ENT was testing for a submucosal cleft that could explain her aspirations and need for nasogastric feeds. Her most recent echocardiogram showed mesocardia with a thickened aortic valve, possibly functionally bicuspid and a moderate dilation of ascending aorta, z +5.1.

From a developmental standpoint, she was limited by her cast. She was making syllable sounds at 6 months and had head control at 4 months corrected for prematurity. She smiled, vocalized, cooed, and babbled reciprocally. She could wave bye, bye, and clap. She does not have words but can recognize names and respond to simple questions with gestures. She sees pulmonology for her breathing concerns and takes multiple medications for her respiratory status. She had a ciliary biopsy to look for signs of a respiratory ciliary defect and this test exhibited 18% abnormal cilia on a small sample size, likely typical for her health and age.

The patient was seen immediately after delivery due to the severity of her non‐immune fetal hydrops. A rapid fluorescent in situ hybridization (FISH) and chromosomal microarray were ordered and both consistent with a normal female result. Given her precarious status in the intensive care unit, she proceeded to have a rapid whole exome sequence. Samples were taken from her biological mother and father as well as the patient. Her testing was performed by a CAP/CLIA certified laboratory using Illumina sequencing. Internal data interpretation is done by analytic pipeline that uses common data sets like gnomAD and ClinVar.

Rapid exome sequencing revealed two variants of uncertain significance (VUS) in NEK8 known to be in trans configuration; NM_178170.3: c.37G>A, p.Gly13Ser inherited from her mother and NM_178170.3: c.1148G>C, p.Arg383Pro inherited from her father. The maternal variant was never documented before and had a CADD score of 31. The paternal variant had a low gnomAD frequency and a CADD score of 32. Both variants are predicted to be deleterious in variant modeling prediction software and her asymptomatic brother was found to harbor only a single variant.

4. DISCUSSION

The given literature on renal‐hepatic‐pancreatic dysplasia type 2 (RHPD2) suggests a core phenotype of birth defects within the liver, heart and kidneys; but with a high degree of variability within the known patients with respect to survival. Median life expectancy before and after birth were limited to 26 weeks and 85 days, respectively. Even with the restricted patient population, the cohort reflected a generalizable group that could make inferences on this disease. Our patient adds to the existing literature both to confirm and suggest further variability to the phenotype (Table 1).

Our patient had significant findings consistent with this disorder, including many seen in the few existing patients. Although her variants were classified as uncertain, her variants meet ACMG variant classification criteria (Richards et al., 2015) to increase pathogenicity. Her variants are in trans and segregate with disease in multiple family members, a moderate pathogenic criterion. Figure 1 summarizes the known NEK8 domains and that these variants fit within well studied functional domains, another moderate pathogenicity criterion. The c. 37G>A variant was absent in population databases, another moderate pathogenicity criterion; and the c.1148G>C variant was seen to change the same amino acid previously reported as pathogenic, which is a strong pathogenicity criterion. There are three additional supporting criteria including: multiple lines of computational evidence, missense variation in a gene with a low rate of benign variants, and the patient's phenotype has a high specificity for this disorder. The existing ACMG criteria concur that the c.37G>A variant is likely pathogenic and c.1148G>C is pathogenic, thus confirming her diagnosis and incorporating these as known variants to cause disease.

This case presents anomalies that had not been previously reported in the literature with RHPD2. Our patient presented with non‐immune fetal hydrops. There have been reports of ciliopathies within the same gene family causing hydrops, but not specifically with variants in NEK8. Casey et al. (2016) described a lethal skeletal dysplasia caused by pathogenic variants in NEK9 and a patient within this cohort had hydrops. Our patient had a hemivertebra, which is unique to this case, but consistent with previously reported skeletal anomalies. Additionally, she had a cloacal anomaly, imperforate anus, and complex abdominal anatomy; and while gastroenterological and urinary tract defects have been reported, these specific anomalies are exclusive to our patient.

Furthermore, her case raised the larger question of interventions and longevity after diagnosis. At the time of diagnosis, most existing papers reported fetal or perinatal demise. In our case, palliative care was discussed given the collection of thirteen deaths in the perinatal period (Al‐Hamed et al., 2016; Frank et al., 2013; Grampa et al., 2016; Lei et al., 2017; Liu et al., 2020; Rajagopalan et al., 2015), but a recent report by Hassan et al. published after our initial discussion suggested improved longevity in a pair of siblings with a NEK8 variant. Unfortunately, both siblings developed end‐stage liver disease with only one undergoing liver transplantation. Hassan's report of the significant and early cardiac and renal disease in the transplanted child suggests a possible progression of NEK8 related disease in these organ systems, regardless of transplantation status. However, the case Vasilescu et al. presented directly contradicts the idea of an inherent and universal progression of cardiac disease in those with RHPD2. Her transplant was successful ten years ago, with only a mild episode of rejection and typical labs to date. Her cardiomyopathy is mild and monitored with a better response to specific medications after transplant. Her case supports the use of transplantation but shows a possible susceptibility to cardiac failure due to NEK8 variants in the context of other factors (i.e., GH). This successful transplantation could help guide future care with patients who have RHPD2 and change the discussion from lethality to viability.

This condition has been previously considered perinatal lethal as demise was noted in over 75% (13 of 17) of patients; resulting from intrauterine fetal demise, termination, or death within the first year of life. We now know of four patients who have lived past the perinatal period. Of these, two have had transplantation with one resulting in long‐term survival. These numbers are only based on known cases, which are likely underreported. There could be a larger subset of patient with RHPD2 that are not identified through genetic testing or not offered transplantation. Furthermore, RHPD2 should be considered in situations in which there is failure of multiple body systems; including cardiac, renal or hepatic. With an increase in uptake of genetic testing, there could be a larger cohort of living patients who would only provide additional data on long‐term outcomes and advance these discussions further.

5. CONCLUSIONS

Our patient was the seventeenth diagnosed with RHPD2 and adds to the existing phenotype of this disorder including non‐immune hydrops, hemivertebra, and cloacal anomaly. Her case also aided in a larger review of the literature for patients surviving past the perinatal period and opened discussion for the use of transplantation in this genetic disorder. There has been a case of successful transplantation and four cases of survival beyond the first year of life in this disease. Those patients who have lived into childhood have displayed typical development and intelligence, demonstrating this condition is associated with anatomic anomalies and not developmental abnormalities. This literature review expands our knowledge of RHPD2 and raises larger questions about how these patients should be managed as they exit the perinatal period and require time intensive surgeries like transplantation. This disorder should not be considered to be perinatal lethal and may well be a variably expressive disorder that exists within a broader group of patients not receiving whole exome sequencing or transplantation.

AUTHOR CONTRIBUTIONS

Kathryn Gunther collected the clinical data, literature research, and writing. Paul R Hillman provided clinical guidance and assisted in manuscript editing. Essam Imseis assisted in manuscript editing and collecting clinical data. Elizabeth Hillman assisted in manuscript editing and collecting clinical data. Joyce Samuel assisted in manuscript editing and collecting clinical data. Tiina Ojala and Timo Jahnukainen, both contributed data on the oldest patient’s clinical picture and edited the manuscript.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

ETHICS STATEMENT

Written informed consent was obtained from the patient for the publication of this case report. The study was approved by an ethics committee and was exempt from IRB approval based on the format of the research. The patient reported in Vasilescu et al. gave informed consent to have de‐identified information reported in this additional study.

Gunther, K. , Imseis, E. M. , Samuel, J. P. , Hillman, E. A. , Ojala, T. H. , Jahnukainen, T. , & Hillman, P. R. (2023). Renal‐hepatic‐pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity. Molecular Genetics & Genomic Medicine, 11, e2135. 10.1002/mgg3.2135

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author, Kathryn Gunther, at Kathryn.a.gunther@uth.tmc.edu. The data are not publicly available as they are private medical information.