Turner syndrome and autosomal dominant polycystic kidney disease

Abstract

Turner syndrome is a chromosomal disorder that involves multiple organ systems and is typically associated with short stature. A multidisciplinary approach with regular screening and surveillance is key to managing this condition’s multiple comorbidities. We present a case of a young girl with Turner syndrome and associated short stature on growth hormone treatment who presented with cystic renal disease found to be autosomal dominant kidney disease. We propose reevaluation of renal screening guidelines in this population due to the potential association of growth hormone and cyst proliferation.

Turner syndrome (TS) is a sex chromosome disorder resulting from the complete or partial loss of one of the X chromosomes.^1,2 This syndrome affects approximately 1 in 2000 to 5000 females.¹ The genetic anomaly results in multisystem disease, which may include malformations of the reproductive, cardiac, integumentary, renovascular, and endocrine systems, among others. Short stature is one of the most common features of TS³ and is commonly treated with growth hormone (GH) with favorable increases in achieved height.² In addition to growth promotion, GH plays a role in regulating the functions of many organs, including the kidneys.⁴ Autosomal dominant polycystic kidney disease (ADPKD) affects approximately 1 in 500 people worldwide.⁵ It is a multisystem disease that characteristically has bilateral renal cysts and an increased risk of intracranial aneurysms, among other manifestations. ADPKD is also an important cause of end-stage renal disease, which affects about half the patients with ADPKD.⁵

CASE PRESENTATION

A 5-year-old girl with TS with 45 XO, diagnosed prenatally via amniocentesis, presented to the nephrology clinic for evaluation of abnormal renal ultrasound findings. Her kidneys were large for age bilaterally (right, 10.0 cm; left, 9.7 cm) without other focal abnormalities. She had been noted to have a small cyst on her left kidney at birth. Her other medical comorbidities included bicuspid aortic valve with dilated aortic root, amblyopia, and short stature treated with GH (somatropin, GH) since the age of 2 years with good clinical response. She had no hypertension, dysuria, frequency, or urgency but did have nocturnal enuresis on occasion. Family history was negative for polycystic kidney disease, hypertension, renal disease, hemodialysis, renal transplant, thoracic aortic dissections, and intracranial aneurysms. As the patient had normal electrolytes and creatinine and no concerning symptoms, yearly renal ultrasound and blood pressure monitoring was advised.

Follow-up ultrasound 1 year later (at age 6 years, 7 months) found a few small bilateral cysts measuring <1 cm (1 cm cortical cyst in the left kidney and two 0.7 cm cysts in the right kidney) and persistent renal enlargement. No concerns regarding hypertension, dysuria, frequency, or urgency were reported. The patient was continuing GH treatment at this time. Creatinine and electrolytes remained normal. An excellent growth pattern persisted with nightly GH injections, and she was instructed to follow up in 1 year, as she was clinically stable.

Subsequent renal ultrasound 1 year later showed larger renal cysts (1.1 cm and 0.9 cm on the right, 1.9 cm and 1.0 cm on the left). Elevated blood pressure readings were noted (systolic blood pressure 92% for age). Due to concerning findings of hypertension and progressive renal cysts with further growth of the kidneys potentially secondary to GH treatment, her endocrinologist and nephrologist decided to stop GH treatments for 6 months.

After 6 months off GH therapy, renal enlargement was unchanged. One of the cysts was unchanged and two others had enlarged. Elevated blood pressure persisted (systolic blood pressure 90% for age). The patient, now age 7, was sent for genetic studies and was found to be heterozygous for a pathogenic variant in the PKD1 gene (c.12010C > Tp.Q4004X) consistent with the diagnosis of ADPKD. Both parents tested negative for the PKD1 mutation, suggestive of de novo mutation. The patient was started on enalapril for blood pressure control.

Follow-up renal ultrasound 6 months later at age 8 showed modified Bosniak type I and II cysts (Figure 1), indicating a malignancy risk of <3%.⁶ The known cysts were similar in size, and a small new cyst was identified. Evaluation, including magnetic resonance imaging/magnetic resonance angiogram imaging of the chest and head without contrast, was unrevealing for aneurysm. There was no evidence of microalbuminuria or proteinuria on her urine studies to date, and her blood pressure improved with enalapril. The patient remains off of GH and the cysts have remained stable.

Figure 1.

Longitudinal and transverse images of the (a) left kidney, showing a septated cyst (Bosniak II) in the left lower pole (calipers), and (b) right kidney, showing a cyst with a thin septation (Bosniak II) in the right lower pole (calipers).

DISCUSSION

This case highlights the potential for patients with TS who are on GH treatment to develop kidney disease. We know that renal malformations commonly occur in patients with TS (30%–40%), with the most common anomalies being collecting system abnormalities or a horseshoe, partially or totally duplicated, or absent kidney.¹ Current research suggests that while single renal cysts are relatively frequent in TS,⁷ multicystic renal disease can occur in up to 2% of patients with TS.^1,8 To our knowledge, the association of TS and ADPKD has not been described. The current clinical practice guidelines endorsed by the American Academy of Pediatrics and Pediatric Endocrine Society state that patients with known TS should receive a renal ultrasound at the time of diagnosis. There are no further guidelines for follow-up renal imaging.¹

GH is a mainstay treatment for girls with TS and is recommended in current clinical practice guidelines for children with TS and evidence of growth failure. Mutation in the PKD1 gene can lead to proliferation of the renal tubular epithelial cells, resulting in the multiple cysts found in ADPKD.^9,10 Some studies suggest that GH may contribute to cystic disease severity in patients with polycystic kidney disease by increasing epithelial proliferation playing a role in mediating tubular cell proliferation of the cystic kidney.^4,9 Other studies have shown that GH has positive effects on renal growth and kidney function.^11–13 This case highlights that current screening guidelines of a renal ultrasound at the time of diagnosis of TS may leave patients with clinical disease undiagnosed or undermanaged, especially those with progressive clinical disease potentially influenced by GH treatment.