Abstract
Among the genes involved in ADKPD, HNF1B encodes a transcription factor implicated in kidneys morphogenesis. Here, we present the case of a little girl with multiple renal cysts diagnosed in utero; at 4 years the genetic testing by NGS revealed the rare pathogenic variant c.1462C > T in the HNF1 gene; additionally, overweight and precocious puberty with appearance of pubic hair were suspected. At 7 years, she was obese with right breast bud, adipomastia and accelerated growth. Our experience highlights the diagnostic difficulties associated with an atypical PKD phenotype and underlines the importance of a holistic approach including diagnosis and early therapies.
Keywords: Autosomal dominant polycystic kidney disease, Next generation sequencing, HNF1 gene, Precocious puberty
1. Introduction
Polycystic Kidney Diseases (PKDs) encompass a broad range of heterogeneous disorders associated with kidney dysfunction.1, 2 Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent renal monogenic disease, affecting around 1 in 1.000 individuals.1 Around 78 % of ADPKD cases are linked to PKD1 gene and around 15 % to PKD2 gene; the remaining 7 % due to variants in other rare genes.3,4 Among the genes involved in the etiopathogenesis of ADPKD, HNF-1b encodes hepatocyte nuclear factor 1, a member of the homeodomain-containing transcription factor family5 that influences the expression of numerous genes including uromodulin (UMOD), fibrocystin (PKHD1), and polycystin-2 (PKD2) in the kidney.4 Mutations in the HNF1B gene are associated with a complex phenotype, likely due to the functional promiscuity of the HNF1b transcription factor which plays a key role in the morphogenesis of several organs, especially kidney, pancreas, and liver.6 The prevalence of HNF1B nephropathy is still poorly understood, but NGS technologies have improved diagnostic yield, allowing for more targeted and effective care and management. Previously, we reported the molecular analysis of a cohort of Italian PKD patients through a targeted NGS gene panel composed of 63 genes, confirming the high degree of genetic heterogeneity.7 Obesity, a chronic disease, is characterized by excessive fat deposits that can adversely affect health8; its prevalence among children and adolescents has increased significantly, reaching epidemic proportions in many countries.9 Here, we describe the case of one little girl who received prenatal ultrasound diagnosis of multicystic kidneys. Additionally, at the age of about 4, she was diagnosed as overweight and was suspected of suffering from precocious puberty.
2. Case presentation
The patient received prenatal ultrasound diagnosis of multicystic left kidney at 20 weeks. After birth, the patient was evaluated at the age of 2 months by cystourethrography and abdominal ultrasound.
The cystourethrography revealed the absence of evident calcium images projecting at the level of the small pelvis. Bladder was of good capacity with regular walls. Absence of post-urination bladder residue. After partial emptying of the bladder, opacification of a tubular-shaped structure compatible with "reflux colpogram" was found. The ultrasound showed right kidney in place, with a volume at the upper limits (55mm), with an inhomogeneous echostructure due to the presence of a 7mm cystic formation at the lower pole, without dilation of the calico-pyelic cavities; left kidney in place, increased in volume (66mm), with a notable reduction of the cortical component, with an inhomogeneous echostructure due to the presence of numerous cystic formations of maximum diameter (24mm, 27mm), without dilation of the calico-pyelic cavities (Fig. 1).
Fig. 1.
Ultrasound image of the case index kidneys at the age of 2 months (A) Right kidney with a 7mm cystic formation at the lower pole (B). Left kidney increased in volume (66mm), with a notable; reduction of the cortical component, with an inhomogeneous echostructure due to the presence of numerous cystic formations of 27 mm maximum diameter.
At the age of 4 years, ultrasound evaluation confirmed the presence of a single cyst in the right kidney and multiple cysts in the left one (maximum diameter 29 mm) (Fig. 2). In detail, the ultrasound revealed right kidney in place with a slightly irregular cortical profile with small incisions, regular shape and slightly increased dimensions (max. diam. 89 mm), with a faint hyperechogenicity of the nephroparenchyma and reduced corticomedullary differentiation. A small oval cortical cystic formation at the meso-renal location (max. diam. 3 mm). Left kidney in place, with dimensions at the lower limits of normal (max. diam. 61 mm) with a subverted echostructure, with absent corticomedullary differentiation and presence of multiple cystic-appearing formations with anechoic content, cortical and para-pyelic (max. diam. 29 mm at the upper polar location, 24 mm both at the mesorenal and lower polar locations). ì.
Fig. 2.
Ultrasound image of the case index kidneys at the age of 4 years (A) right kidney with slightly increased dimensions (max. diam. 89 mm) and a single cyst (max. diam. 3 mm). (B). left kidney with dimensions at the lower limits of normal (max. diam. 61 mm) and a subverted echostructure with multiple cysts (maximum diameter 29 mm).
Clinical and biochemical evaluations were performed periodically (see Table 1). eGFR, creatinine and azotemia levels were in the normal range while cystatin was at the upper range. Mg is at the lower part of the range.
Table 1.
Over time anthropometrical and biochemical features of the case index GP.
| Index | 2 months | 1-Y old | 2-Y old | 3-Y old | 4-Y old | 5-Y old | 6-Y old | Reference index |
|---|---|---|---|---|---|---|---|---|
| Weight (kg) | 3.070 | 11.270 | 17.57 | 19.7 | 23 kg (90°) | 27.7 kg (97°) | 33 (97°) | – |
| Height (cm) | 50 | 79 | 94.5 | 101.5 | 105.5 (50–75°) | 114 (51°) | 120.5 (50°–75°) | – |
| BMI | – | – | – | – | 20.8 (99°) | 21.1 (98°) | – | |
| Growth speed | – | – | – | – | 3.6 cm/7 months (normal) | – | 5.8 cm/year (normal) | – |
| Creatinine (mg/dL) | 0.32 | 0.36 | 0.37 | 0.36 | 0.41 | 0.43 | 0.4 | 0.2–0.45 |
| Azotemia (g/dL) | 26 | 43 | 63 | – | – | – | – | – |
| eGFR (ml/min/1.73m^2 | 83 | 91 | 105 | 116 | 108 | 118 | 124 | – |
| Uricemia (mg/dL) | 5.6 | 6.4 | 6.2 | 6.1 | 6.9 | 6 | 4.2 | 2.4–5.7 |
| Albumin (g/dL) | – | – | – | 4.1 | 4.5 | 4.3 | 4.3 | 3.4–4.8 |
| Alb/Glob | – | – | – | 1.5 | 1.3 | 1.4 | – | 1.2–2.4 |
| Cystatin (mg/dL) | – | – | – | 1.18 | – | 1.05 | 1.27 | 0.61–1.1 |
| Proteins Tot (g/dL) | – | – | – | 6.8 | 8 | 7.3 | 7.6 | 6–8 |
| Mg (mg/dL) | – | – | – | 1.5 | 1.9 | 1.6 | 1.6 | 1.6–2.6 |
| Iron (g/dL) | 73 | 83 | 68 | 66 | 114 | 75 | 95 | 30–120 |
| Urea (mg/dL) | – | – | – | 41 | 45 | – | 36 | 10–38 |
| Glucose (mg/dL) | – | – | – | 75 | 98 | 97 | 89 | 60–110 |
| Cholesterol (mg/dL) | – | – | – | 123 | – | 154 | 162 | 100–180 |
| Triglycerides (mg/dL) | – | – | – | 99 | – | 50 | 47 | 35–90 |
| CRP (mg/L) | 0.12 | 0.156 | 0.56 | 5.29 | 0.99 | 0.95 | 1.82 | 0–5 |
| RBC (x10^6/μl) | 4.6 | 4.5 | 4.53 | 4.73 | 5.02 | 4.75 | 4.69 | 3.9–5.2 |
| HGB (g/dL) | 12.40 | 11.5 | 12.3 | 12.7 | 13.1 | 12.7 | 12.2 | 10.5–14 |
| WBC (x10^3/μL) | 10.49 | 8.82 | 10.85 | 7.54 | 9.73 | 7.55 | 8.06 | 5–15.5 |
At the same age, the patient was overweight, 23 kg, (90°), h 105.5 cm (50°–75°) (Table 1) and suspected of suffering from precocious puberty with appearance of pubic hair. Table 2 reports hormonal data of the patient: ACTH, Cortisol, Testosterone levels and 17OH-Progesteron were lower, while DHEA-S levels were higher.
Table 2.
Hormonal characterization of the case index GP.
| Hormone | 6-Y old | Reference index |
|---|---|---|
| Parathormone (pg/mL) | 48.54 | 15–65 |
| TSH (ul/U/mL) | 2.04 | 0.500–4.800 |
| FT3 (Pg/mL) | 3.7 | 2.5–5.20 |
| FT4 (ng/dL) | 1.43 | 0.93–1.70 |
| 17OH-Progesterone (ng/mL) | 0.01 | <0.26–1.48 |
| DHEA-S (μg/dL) (ug/dL) | 86.11 | 2.80–85.00 |
| Testosterone (ng/mL) | <0.02 | 0.06–0.82 |
| Cortisol (ug/dL) | 0.34 | 4.8–19.50 |
| ACTH (pg/mL) | 4.88 | 7.00–28.00 |
| Delta 4 Androstenedione (ng/mL) | <0.24 | 0.10–2.41 |
The molecular analysis for PKD was performed by a NGS gene panel consisting of 63 genes related to PKD on genomic DNA, isolated from peripheral blood.10 NGS revealed the rare c.1462C > T p. (Gln488Ter) mutation in heterozygosity in HFN1b gene. The variant was confirmed by Sanger on a second patient's genomic DNA. The mutation is a single base variant located in exon 7; it consists of a nonsense change at residue 488 (p.Gln488Ter) that introduces a premature stop codon into the protein resulting in the creation of a truncated protein. According to the American College of Medical Genetics and Genomics guidelines, the variant is classified as likely pathogenic (PVS1 and PM2) and reported in the Varsome and Franklin databases. At 7 years, appearance of with right breast bud and adipomastia was registered. Hormonal evaluations revealed normal thyroid hormones while low testosterone, 17-OH progesterone, ACTH and cortisol levels. In addition, high DHEA levels were found. In parallel, the patient parents and the sister came to our attention. The mother, 35 years old, clinically presented multiple cysts in both kidneys and no obvious abnormality was detected in other organs. After genetic counselling, the mother, father and sister of the patient were analysed: the c.1462C > T mutation of the HNF1B gene was detected in the mother.
Fig. 3 shows the clinical and genetic diagnosis of the patient.
Fig. 3.
Representation of the clinical and genetic diagnosis of the patient.
3. Discussion
The HNF1B gene encodes a transcription factor, member of the homeodomain-containing transcription factor family, which plays a key role in the morphogenesis of several organs, especially the kidney.11 Mutations in the HNF1B gene are associated with a rare autosomal dominant monogenic disease characterized by a broad and variable multisystem phenotype.6,10 Here, we describe the case of a newborn who was diagnosed with PKD and who has maintained normal kidney function to date. Using the NGS approach10 the rare mutation c.1462C > T p. (Gln488Ter) in heterozygous in the HFN1B gene located in exon 7 was identified; it consists of a nonsense modification in residue 488 (p.Gln488Ter) and gives rise to a truncated protein. Exon 7 of the HNF1B gene encodes part of the protein's transactivation domain which is crucial for the protein's ability to activate or repress gene transcription. Previously, single nucleotide variants and deletions of HNF1B, including entire gene deletions, have been reported in literature as constituting the genetic basis of HNF1B nephropathy.12 Given the autosomal dominant genetic inheritance of HFN1B, after molecular analysis of the patient's family, we identified the c.1462C > T mutation in the mother, who presented multiple renal cysts on ultrasound analysis.
At the age of 4, the patient was diagnosed as overweight and suspected of suffering from precocious puberty with appearance of pubic hair. At 7 years, BMI was 21.1 (98 %), with right breast bud and adipomastia; accelerated linear growth. Childhood obesity represents a multifaceted challenge to endocrine health and may be associated with precocious puberty, which affects physical growth, psychosocial development and increases the risk of metabolic diseases.13 Furthermore, obesity is often associated with increased reactivity of the hypothalamic-pituitary-adrenal axis. In the case of the patient, adrenal pathology has been excluded, while low plasma cortisol levels, testosterone and ACTH levels, high levels of DHEA-S with a normal thyroid functioning are observed.
Previously, we reported the NGS analysis of PKD patients through our targeted gene, confirming the high degree of genetic heterogeneity and arguing that different pathogenic mutations in different genes could be the molecular basis of the same clinical phenotype of PKD patients.10
In conclusion, we describe a rare case of a little patient affected by PKD due to HNF1B gene's mutation. The clinical phenotype was characterized by numerous renal cysts and renal enlargement, a clinical picture commonly associated with ADPKD and at high risk of rapid progression to renal failure nephropathy. The concomitant presence of precocious puberty is not reported in the literature as a clinical manifestation associated with HNF1B, but was present in our patient, delineating the identification of a new clinically relevant implication that could transfer the evolving paediatric knowledge to adult clinicians. The complex relationship between PKD, obesity and endocrine pathways should require a holistic approach that includes prevention, diagnosis and early therapeutic treatment to reduce the risk of even serious complications, especially in children as in the case presented in this work. In summary, our case highlights on the one hand the diagnostic difficulties associated with an atypical phenotype in a girl with PKD carrying a variant of the HNF1B gene and, on the other hand, does not clarify whether the development of precocious puberty and obesity are a manifestation associated with the HNF1B gene mutation or another unidentified aetiology.
CRediT authorship contribution statement
Ersilia Nigro: Writing – review & editing, Writing – original draft, Data curation. Rosamunda D'Arcangelo: Writing – original draft, Formal analysis, Data curation. Antonio Pisani: Writing – review & editing, Data curation. Gabriele Malgieri: Writing – review & editing, Data curation. Aurora Daniele: Writing – review & editing, Writing – original draft, Supervision, Conceptualization.
Informed consent to participate
The authors received the informed consent of the legal guardians of the affected individual prior to all conducted analyses as well as for the publication of genetic and clinical data.
Ethics statement
This study adheres to the principles set out in the Declaration of Helsinki.
Funding acknowledgement
No fundings received.
Conflict of interests
The authors declare no conflict of interest.
Acknowledgments
We thank the patient's family.
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