The index case, 2 siblings and his parents underwent clinical, biochemical and genetic analyses. The index case is the oldest sibling and aged 7 at the time of hospital admission for diagnostic work-up as his younger sister had been diagnosed with nephrocalcinosis and hypomagnesaemia, aged 18 months. She was first thought to have renal problems at the age of 18 months, having been investigated for failure to thrive from the age of 10 months. She had recurrent urinary tract infections and was shown to have reflux into one ureter and impaired renal function. She did not have hypertension at the time of presentation and did not require anti-hypertensive treatment until later when she was started on Atenolol 25 mg/daily. Her blood pressure was subsequently well controlled on this treatment. Unlike his younger sister, the index case had not had any acute presentations necessitating hospital admissions earlier. He had been generally well but closer questioning revealed a history of polyuria/polydipsia, unexplained feverish illnesses, possibly due to frequent urinary tract infections since early childhood. In contrast to his younger sibling, he had marked hypertension. Physical examination revealed arterial hypertension (B.P 170/130 mmHg). His height was 126.6 cm (75th centile) and his weight 23.5 kg (50th centile). Examination of his heart, lungs, abdomen and nervous system was unremarkable. There was no evidence of ocular abnormalities or hearing impairment. They are Caucasians and there was no history of parental consanguinity.
Preliminary laboratory investigations in the index case revealed renal impairment (sodium: 142 mmol/L, potassium: 3.6 mmol/L, urea: 7.1 mmol/L, creatinine: 93 mcmol/L, GFR: 51 mls/min/1.73 m2). Serum calcium was normal (2.38 mmol/L), magnesium was low (0.63 mmol/L, reference range 0.7–1.0 mmol/l), phosphate was 1.52 mmol/L. Parathyroid hormone (PTH) was elevated, 600 ng/L (normal range: < 120). Urinary analyses revealed hypercalciuria, 5.67 mmol/24 hours (normal range: < 2.5/24 hours). Fractional excretion rate of magnesium was elevated: 12.4% (< 4%). Water deprivation test indicated a defect in urinary concentrating ability. Ammonium chloride loading test revealed a distal defect in urinary acidification. Abdominal plain radiographs revealed bilateral nephrocalcinosis and large kidneys. Based on the clinical and laboratory findings a diagnosis of FHHNC was made. Treatment was started with magnesium supplementation and chlorothiazide. The hypercalciuria was resistant to chlorothiazide which was later discontinued as it aggravated hypomagnesaemia. He was also treated with propanolol 40 mg three times daily and hydralazine 3.5 mg three times daily. His blood pressure was satisfactory on these medications and came down to 100/60. The index case's growth rate was not compromised to the same extent as his younger sibling. Treatment, however failed to prevent the progression of renal failure in both children. They eventually underwent renal transplantation. The younger sibling required renal transplantation at an earlier age as the decline in GFR was more rapid in her case compared to her older sibling whose renal functions were better preserved. Her GFR was 27 mls/min at age 5, having declined from 32 ml/min in 2 years. Her pre-transplant results at age 9 years showed normal serum electrolytes, urea: 35.2 mmol/L, creatinine: 454 mcmol/L, calcium: 1.69 mmol/L, phosphate: 1.69 mmol/L, magnesium: 0.73 mmol/L. The affected younger sibling received a deceased donor transplant. In contrast the index case's GFR remained stable at 40 ml/min during his early teenage years. However his renal function declined further in his late teens and he received a live donor kidney in young adulthood from his father.
All subjects, including the index case and his affected younger sibling who are now adults aged 33 and 28 years respectively gave their consent. The parents and the unaffected sibling were also screened. The parents and unaffected child's biochemical results were normal. They had no history of renal calculi. Urinary calcium, magnesium and phosphate excretion was normal. Blood was also obtained from all members of the family for genetic analyses after informed consent. This had been approved by the Research Ethics Committee of Guy's Hospital, UK. Consent for publication was obtained from the patients.