Oral Presentation 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

Chronic kidney disease-mineral and bone disorder (CKD-MBD) and delayed puberty: a case of renal and gonadal dysgenesis (#43)

Genevieve L Calder 1 , Dilan Seneviratne Epa 1 , Jasna Aleksova 1 2 , Richard J MacIsaac 1
  1. Department of Endocrinology and Diabetes, St Vincent's Hospital, Melbourne, VIC, Australia
  2. Hudson Institute , Clayton, Victoria, Australia

 

A 23-year-old woman (Ms A) from rural Victoria was referred with complex metabolic bone disease. 

Ms A had a history of congenital dysplastic kidneys requiring peritoneal dialysis from age eight months and live renal transplant at age three years. Her immunosuppressive therapy was complicated by avascular necrosis of the right hip at age 4 years. Subsequently, there was a slow deterioration in graft function from mid-adolescence in the setting of non-adherence to immunosuppression and follow-up. Haemodialysis was ultimately commenced at age 20 years. She has required regular calcium carbonate and calcitriol for secondary hyperparathyroidism (SHPT). However, multiple hospital admissions have been necessary for symptomatic hypocalcaemia due to ongoing inadequate treatment adherence. She had no history of fractures

In the six months preceding her presentation, Ms A had abruptly developed progressive bilateral genu valgum [Figure 1], bilateral bowing of her tibiae and new thoracic kyphosis. These deformities were painful and now limited her capacity to ambulate and drive.

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Upon further history, Ms. A also had un-investigated primary amenorrhoea. She underwent adrenarche at age 10 years, but not thelarche or menarche. There was no significant family history.

She had completed high school and had worked in agriculture until just before our review when her skeletal deformities became too debilitating. She was single, not sexually active, a non-smoker and did not drink alcohol or use illicit drugs.

On examination, her height was 157cm and weight 63kg, giving her a BMI of 25.6kg/m2. Her Tanner stages for breast and pubic hair development were I and III respectively and she had female external genitalia.

At presentation, biochemistry [Table 1] confirmed severe SHPT. Parathyroid hormone (PTH) levels had been persistently elevated (>20 times the upper limit of normal) for years prior, associated with hyperphosphataemia and normal/low corrected calcium, despite high calcium dialysis baths, phosphate binders and vitamin D supplementation. Bone turnover markers were also significantly elevated, but are known to accumulate in patients on dialysis. Hypergonadotrophic hypogonadism was confirmed with normal serum androgens and other pituitary hormones.

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Skeletal survey revealed multiple Brown’s tumours, osteomalacia and alternating bands of sclerosis and lucencies throughout the lumbar spine (classical ‘rugger-jersey’ appearance) [Figure 2]. Un-fused epiphyses were observed throughout her skeletal survey [Figure 3]. Pelvic ultrasound and magnetic resonance imaging (MRI) demonstrated a hypoplastic rudimentary uterus with no ovaries or streak gonads. Karyotype analysis was 46, XY.

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In the setting of gonadal and renal dysgenesis, a genitourinary embryological disorder, such as Denys-Drash Syndrome (DDS) or Frasier Syndrome, was suspected. Given her renal failure manifested as an infant, DDS was considered the more likely diagnosis. Wilm’s Tumour-1 suppressor gene (WT-1) mutation analysis is currently pending but will be available prior to case presentations.

Her metabolic bone disease was multifactorial including SHPT, osteomalacia, renal metabolic acidosis and anaemia, prolonged past glucocorticoid exposure and primary gonadal failure.

A multidisciplinary approach has been undertaken for her management. Supervised administration of phosphate binders, calcitriol and cholecalciferol with intensified dialysis has been implemented to attenuate her secondary hyperparathyroidism and osteomalacia. Ms A was counselled regarding her genetic sex and given that she identified as a female, pubertal induction was commenced with topical estradiol 25mcg/24hr with the plan to gradually increase this dose. Consideration of orthopaedic correction of her genu valgum is ongoing. Laparoscopic investigation of dysmorphic gonadal tissue is planned and vaginoplasty for short vagina will be discussed. A second renal transplant will be the ultimate management of both her CKD if medication adherence is established.

 

Discussion

DDS is a rare condition caused by mutations in the WT-1 gene (chromosome 11p13), which is involved in renal and gonadal development. The estimated prevalence is <1/10,000. Clinically, DDS presents as a triad of early onset, steroid-resistant nephrotic syndrome leading to end stage kidney disease (ESKD); intersex disorders with risk of gonadoblastoma; and Wilms’ tumour.1 Incomplete DDS involving ESKD and intersex disorders (similar to this case) or Wilms’ tumour have also been described.2 Mutations in the WT-1 gene may also cause Frasier Syndrome, but this leads to more indolent kidney failure. The clinical features of both disorders are compared in Table 2.

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Long term graft outcomes of DDS do not differ from the general paediatric kidney transplant patients.2 Total nephrectomy is routinely performed when ESKD develops to prevent Wilms’ tumour development. Prophylactic gonadectomy is also considered given risk of gonadoblastoma, especially in patients with XY gonadal dysgenesis.4

Delayed puberty is commonly encountered in adolescent patients with CKD.5 However, in children with a functioning renal transplant, the mean age at menarche is equivalent to healthy females.6 Linear growth failure is also a frequent complication and is age dependent: the younger the onset of CKD, the more severe the growth failure.7 The pathophysiology is multifactorial including energy malnutrition, metabolic acidosis, renal anaemia, glucocorticoid exposure, hypothalamic-hypogonadism and growth hormone resistance. Growth failure may manifest despite conservative, dialysis or transplant treatment.8

CKD-MBD is characterised by systemic abnormalities in bone and mineral metabolism and/or extra-skeletal calcification. As renal function deteriorates, increasing perturbations in calcium, phosphate, fibroblast growth factor-23, PTH and vitamin D homeostasis occur. Abnormalities in bone turnover, mineralisation and volume occur [Table 3]. In children, CKD-MBD may result in growth failure as well as bone-specific morbidity, including fractures and painful and debilitating deformities.9

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Hypogonadism is a frequent finding in patients with CKD and exerts an additive effect on bone abnormalities in CKD-MBD. In pre-menopausal women with ESKD, hypogonadism has been associated with higher bone turnover and more significant bone mass decrements than in eugonadal states.10

Paediatric CKD-MBD treatment paradigms aim to minimize complications to the growing skeleton and extra-skeletal calcification. Adequate phosphate binders and vitamin D sterol supplementation attenuate hyperphosphataemia and SHPT. The PTH level should be maintained at 2-9 times the upper limit of the reference range due to PTH resistance exhibited in uraemic bones. Adequate sex steroids increase BMD in hypogonadal pre-menopausal women and pubertal induction may be necessary.10 Successful renal transplantation reverses many of the metabolic and mineral changes of CKD and offers the greatest reduction in morbidity and mortality.9

  

 

 

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