Susan P. A. Rigden

Characterization of GATA3 Mutations in the Hypoparathyroidism, Deafness, and Renal Dysplasia (HDR) Syndrome

The hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. The C-terminal zinc finger (ZnF2) binds DNA, whereas the N-terminal finger (ZnF1) stabilizes this DNA binding and interacts with other zinc finger proteins, such as the Friends of GATA (FOG). We have investigated seven HDR probands and their families for GATA3 abnormalities and have identified two nonsense mutations (Glu-228 → Stop and Arg-367 → Stop); two intragenic deletions that result in frameshifts from codons 201 and 355 with premature terminations at codons 205 and 370, respectively; one acceptor splice site mutation that leads to a frameshift from codon 351 and a premature termination at codon 367; and two missense mutations (Cys-318 → Arg and Asn-320 → Lys). The functional effects of these mutations, together with a previously reported GATA3 ZnF1 mutation and seven other engineered ZnF1 mutations, were assessed by electrophoretic mobility shift, dissociation, yeast two-hybrid and glutathione S-transferase pull-down assays. Mutations involving GATA3 ZnF2 or adjacent basic amino acids resulted in a loss of DNA binding, but those of ZnF1 either lead to a loss of interaction with specific FOG2 ZnFs or altered DNA-binding affinity. These findings are consistent with the proposed three-dimensional model of ZnF1, which has separate DNA and protein binding surfaces. Thus, our results, which expand the spectrum of HDR-associated GATA3 mutations and report the first acceptor splice site mutation, help to elucidate the molecular mechanisms that alter the function of this zinc finger transcription factor and its role in causing this developmental anomaly.

THE INFLUENCE OF STEROID THERAPY AND RECOMBINANT HUMAN ERYTHROPOIETIN ON THE GROWTH OF CHILDREN WITH RENAL DISEASE

Long-term steroid therapy has a depressant effect on hypothalamo-pituitary pulsatile secretion of growth hormone (GH), and this results in an attenuated pubertal growth spurt. Oxandrolone and recombinant human GH improve growth rates in children taking long-term steroid therapy for renal disease, but there are potential side effects. Treatment with recombinant human erythropoietin improved the growth of three prepubertal, but not three pubertal haemodialysis patients.

Growth over 10 years following a 1-year trial of growth hormone therapy.

Abstract The growth of short children with chronic renal failure (CRF) and renal transplants was assessed over 10 years following entry into a 1-year trial of recombinant human growth hormone (rhGH) therapy. Patients were divided into three groups: 6 prepubertal patients with CRF (group 1), mean (range) age at start of trial 7.7 (5.0–10.4) years; 6 prepubertal patients with renal transplants (group 2), age 11.9 (9.5–14.6) years; and 6 pubertal patients with renal transplants (group 3), age 15.6 (14.1–18.3) years. In group 1, the mean (range) height standard deviation score (Ht SDS) increased from –2.9 (–3.7 to –2.2) to –1.9 (–2.9 to –0.5) over 4.0 (0.3–9.1) years of rhGH (P=0.04), and was –1.6 (–2.9 to –0.4) after 10 years of follow-up (NS). In group 2 Ht SDS increased from –3.3 (–4.5 to –1.9) to –2.9 (–5.4 to –0.5) over 2.7 (1.0–6.0) years and was –3.0 (–6.3 to –0.1) at final height (NS). In group 3 Ht SDS increased from –3.4 (–4.3 to –2.6) to –3.0 (–3.4 to –2.2) over 1.4 (0.2–2.3) years (NS) and was –2.5 (–3.0 to –1.9) at final height (P=0.03 from stopping rhGH to final height). Final height was attained in 13 patients, in whom Ht SDS increased from –3.2 (–4.3 to –1.9) to –2.6 (–3.9 to –0.5) on rhGH (P=0.004) and to –2.2 (–4.4 to –0.1) after stopping treatment (P=0.04). Four patients died, 2 have chronic hepatitis C, and 1 has had surgery for parathyroid adenomata. In conclusion, the majority of patients had an improvement in Ht SDS while on rhGH, which was maintained after stopping treatment.

Long-term suppression of hyperparathyroidism by phosphate binders in uremic children.

Forty-five children with stable chronic renal failure, not on dialysis, were treated conservatively with a regimen of mild dietary phosphate restriction and high-dose phosphate binders for up to 5 years. Both aluminum hydroxide and calcium carbonate were used initially, but almost all patients were taking calcium carbonate towards the end of the period. Serum immunoreactive parathyroid hormone concentrations were significantly decreased and were within the normal range after 1 year and remained normal during treatment. There was no significant change in renal function over the same treatment period. We conclude that calcium carbonate should be used as the phosphate binder of choice in the long-term suppression of hyperphosphatemia and hyperparathyroidism in uremic children.

Differential effects of recombinant human growth hormone on glomerular filtration rate and renal plasma flow in chronic renal failure

In normal subjects recombinant human growth hormone (rhGH) increases glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) through the action of insulin-like growth factor-I (IGF-I). We have measured clearance of inulin and para-aminohippuric acid in 18 children with chronic renal failure (CRF) during their 1st year of rhGH treatment to look at the immediate (first 3 h), short-term (1 week) and long-term (1 year) effects of treatment. On day 1 mean (range) age was 9.1 (4.9–13.9) years, GFR 19 (9–58) and ERPF 77 (34–271) ml/min per 1.73 m2. During treatment height velocity increased from 4.5 (1.7–6.5) to 9.5 (4.8–12.7) cm/year (P<0.0001). Two children required dialysis after 0.75 years and 1 child was electively transplanted after 0.5 years. There were no other serious adverse events. GFR and ERPF were unchanged in the 3 h following rhGH. GFR remained constant on day 8, 22 (6–56) and after 1 year, 20 (9–59) ml/min per 1.73 m2. ERPF increased to 96 (33–276) ml/min per 1.73 m2 on day 8P=0.005), and remained elevated, but not significantly so, at 99 (24–428) ml/min per 1.73 m2 at 1 year. Fasting IGF-I increased from 147 (46–315) ng/ml to 291 (61–673) by day 8P<0.003), and to 341 (101–786) ng/ml at 1 year. There was no correlation between the change in IGF-I and renal function. Blood pressure, albumin excretion and dietary protein intake were unchanged by treatment. The significance of increased ERPF after 1 week of rhGH in CRF is unclear, but long-term follow-up of renal function is indicated.

Bilateral laparoscopic nephrectomy with simultaneous peritoneal dialysis: a new era

Peritoneal dialysis is the treatment of choice in children with end-stage renal failure who are awaiting renal transplantation. Traditionally patients requiring bilateral nephrectomy spent time on haemodialysis prior to being converted to peritoneal dialysis during a separate operation. Bilateral synchronous retroperitoneoscopic nephrectomy with the initiation of or return to peritoneal dialysis in the immediate postoperative period was performed on three patients with end-stage renal failure in our unit. The indications for bilateral nephrectomy were persistent heavy proteinuria in two children and difficult to control hypertension in the third. Bilateral laparoscopic nephrectomy was performed with the patients in the prone position. Two of the children were then placed in a supine position and a tunneled peritoneal dialysis catheter was inserted in the standard open fashion. The postoperative complications included a peritoneal catheter line breach requiring intraperitoneal antibiotics and a fever that was culture negative and settled spontaneously. This technique allows for immediate peritoneal dialysis, with the added benefit of reduced postoperative pain and improved cosmetic appearance.

Nutritional Management of Infants and Toddlers with Chronic Renal Failure

Normal renal function is an essential prerequisite for normal nutrition. Renal failure results in malnutrition and growth retardation, which are particularly marked when renal failure has its onset early in life. Conversely, the careful application of nutritional therapy can ameliorate the effects of renal failure and allow improved well being and growth and possibly retard the rate of progression of renal failure. Nutritional therapy includes the provision of an adequate energy intake, appropriate intakes of water, electrolytes, vitamins and minerals and regulation of protein and phosphorus intakes. In this paper the theoretical considerations underlying these objectives are reviewed and practical ways of achieving them with least disruption to the child and his family suggested.

OXANDROLONE FOR DELAYED PUBERTY IN BOYS TAKING LONG-TERM STEROID-THERAPY FOR RENAL-DISEASE

Eleven boys, mean age 15.3 years (range 13.2–17.5), with pubertal delay in association with steroid therapy for steroid-sensitive nephrotic syndrome and following renal transplantation were treated with oxandrolone 2.5 mg daily for a mean of 0.50 years (range 0.34–0.61). Mean growth velocity increased from 3.9 cm/year (range 1.1–6.3) to 6.1 cm/year (range 2.0–14.4) and was maintained at 6.1 cm/year (range 0.4–10.2) (P<0.05). However, there was no significant difference in growth between the treated boys and age- and puberty-matched controls. Elevation of blood cyclosporin A and creatinine levels occurred in the transplant patients. Oxandrolone may initiate a pubertal growth spurt in patients taking steroid therapy for renal disease, but should be used with extreme caution because of potential side-effects.

Phaeochromocytoma: report of three cases

The diagnosis and investigation of phaeochromocytoma was reviewed in three patients presenting to the paediatric renal centre with malignant hypertension. The initial diagnosis was made using urinary 4-hydroxy-3-methoxymandelic acid (VMA) and plasma adrenaline and non-adrenaline estimations. Our experience of the localization of phaeochromocytoma with ultrasound,131I-meta-iodobenzylguanidine (MIBG) and venous sampling was discussed and we have reappraised our approach to the localization of these tumours.

Alport's syndrome and hereditary motor and sensory neuropathy type I--an unfortunate coincidence.

A 15-year-old boy with Alports syndrome and hereditary motor and sensory neuropathy type I is described. An association between hereditary motor and sensory neuropathy and a nephropathy has been reported in 12 cases in the literature. Although showing features in common with Alports syndrome and with a familial tendency, these 12 cases are clinically and histologically distinct from our patient who is the unfortunate inheritor of two genetic disorders, one maternally and one paternally derived. Recognition of an association between nephropathy and neuropathy, although rare, is important.