A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis.

Nephropathic cystinosis, an autosomal recessive disorder resulting from defective lysosomal transport of cystine, is the most common inherited cause of renal Fanconi syndrome. The cystinosis gene has been mapped to chromosome 17p13. We found that the locus D17S829 was homozygously deleted in 23 out of 70 patients, and identified a novel gene, CTNS, which mapped to the deletion interval. CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. Eleven different mutations, all predicted to cause loss of function of the protein, were found to segregate with the disorder.

Extending the clinical research network approach to all of healthcare.

The development of Clinical Research Networks (CRN) has been central to the work conducted by Health Departments and research funders to promote and support clinical research within the NHS in the UK. In England, the National Institute for Health Research has supported the delivery of clinical research within the NHS primarily through CRN. CRN provide the essential infrastructure within the NHS for the set up and delivery of clinical research within a high-quality peer-reviewed portfolio of studies. The success of the National Cancer Research Network is summarized in Chapter 5. In this chapter progress in five other topics, and more recently in primary care and comprehensively across the NHS, is summarized. In each of the 'topic-specific' networks (Dementias and Neurodegenerative Diseases, Diabetes, Medicines for Children, Mental Health, Stroke) there has been a rapid and substantial increase in portfolios and in the recruitment of patients into studies in these portfolios. The processes and the key success factors are described. The CRN have worked to support research supported by pharmaceutical, biotechnology and medical device companies and there has been substantial progress in improving the speed, cost and delivery of these 'industry' studies. In particular, work to support the increased speed of set up and delivery of industry studies, and to embed this firmly in the NHS, was explored in the North West of England in an Exemplar Programme which showed substantial reductions in study set-up times and improved recruitment into studies and showed how healthcare (NHS) organizations can overcome delays in set up times when they actively manage the process. Seven out of 20 international studies reported that the first patient to be entered anywhere in the world was from the UK. In addition, the CRN have supported research management and governance, workforce development and clinical trials unit collaboration and coordination. International peer reviews of all of the CRN have been positive and resulted in the continuation of the system for a further 5 years in all cases.

Secondary nephrogenic diabetes insipidus as a complication of inherited renal diseases.

BACKGROUND/AIMS: Nephrogenic diabetes insipidus (NDI) is a serious condition with large water losses in the urine and the risk of hypernatremic dehydration. Unrecognized, repeated episodes of hypernatremic dehydration can lead to permanent brain damage. Primary NDI is due to mutations in either AVPR2 or AQP2. NDI can also occur as a secondary complication, most commonly from obstructive uropathy or chronic lithium therapy. We observed NDI in patients with inherited tubulopathies and aimed to define the clinical and molecular phenotype. METHODS: We reviewed the medical notes of 4 patients with clinical NDI and an underlying molecularly confirmed diagnosis of nephropathic cystinosis, Bartter syndrome, nephronophthisis and apparent mineralocorticoid excess, respectively. RESULTS: The patients all failed to concentrate their urine after administration of 1-desamino[8-D-arginine] vasopressin. None had an identifiable mutation in AVPR2 or AQP2, consistent with secondary NDI. Patients experienced repeated episodes of hypernatremic dehydration, and in 2 cases, NDI was initially thought to be the primary diagnosis, delaying recognition of the underlying problem. CONCLUSION: The recognition of this potential complication is important as it has direct implications for clinical management. The occurrence of NDI in association with these conditions provides clues for the etiology of aquaporin deficiency.

Vasopressin type 2 receptor V88M mutation: molecular basis of partial and complete nephrogenic diabetes insipidus.

BACKGROUND/AIMS: Mutations in the type 2 vasopressin receptor gene (AVPR2) underlie X-linked recessive nephrogenic diabetes insipidus (NDI). Here, we report on a family with a mutation in AVPR2, c.262G>A (p.V88M). This recurrently identified mutation was previously shown to abolish AVPR2 function, yet in some affected members, urine osmolalities of up to 570 mosm/kg were observed. We detail the variable clinical phenotype and investigate its molecular basis. METHODS: Retrospective analysis of clinical data and in vitro assessment of wild-type and V88M-mutant receptors. RESULTS: Clinical data were available on 6 patients. Four of these demonstrated a substantial increase in urinary concentration after 1-desamino[8-D-arginine] vasopressin, consistent with partial NDI, while 2 did not respond. In vitro analysis revealed a reduced cell surface expression and decreased binding affinity for arginine-vasopressin of the mutant receptor, leading to blunted signaling activity. Treatment with the pharmacological chaperone SR121463 enhanced cell surface expression. CONCLUSION: The V88M mutation is associated with phenotypical diversity, which may be explained by the fact that both the expression level and the hormone-binding affinity are affected by the mutation. Our results provide a rational basis for treatment trials with vasopressin analogues in combination with pharmacologic chaperones in patients with this recurrently identified mutation.

The orthopaedic management of lower limb deformity in hypophosphataemic rickets.

BACKGROUND: Many patients with X-linked hypophosphataemic rickets (X-LHPR) demonstrate significant lower limb deformity despite optimal medical management. This study evaluates the use of guided growth by means of hemi-epiphysiodesis to address coronal plane deformity in the skeletally immature child. METHODS: Since 2005, 24 patients with X-LHPR have been referred to our orthopaedic unit for evaluation. All patients had standardised long leg radiographs that were analysed sequentially before and after surgery if any was performed. The rate of correction of deformity was calculated based on peri-articular angles and diaphyseal deformity angles measured at regular intervals using Traumacad software. Clinical records were reviewed to obtain relevant clinical and demographic details. Statistical analysis was performed using SPSS 23 (SPSS Inc., Chicago, IL, USA). RESULTS: The indication for surgical intervention was a mechanical axis progressing through Zone 2 or in Zone 3 despite one year of optimised medical treatment. The 15 patients underwent 16 episodes of guided growth (30 limbs, 38 segments) at a mean age of 10.3 years. In four limbs, surgery has only taken place recently; and in three limbs, correction is ongoing. Neutral mechanical axis was restored in 16/23 (70%) limbs: six improved and one limb (one segment) required osteotomy for residual deformity. The mean rate of angular correction per month was 0.3° for the proximal tibia and 0.7° for the distal femur. Patients with ≥ 3 years of growth remaining responded significantly better than older patients (p = 0.004). Guided growth was more successful in correcting valgus than varus deformity (p = 0.007). In younger patients, diaphyseal deformity corrected at a rate of 0.2° and 0.6° per month for the tibia and the femur, respectively. There has been one case of recurrent deformity. Patients with corrected coronal plane alignment did not complain of significant residual torsional malalignment. Serum phosphate and alkaline phosphatase levels did not affect response to surgery. CONCLUSIONS: Guided growth is a successful, minimally invasive method of addressing coronal plane deformity in X-LHPR. If coronal plane deformity is corrected early in patients with good metabolic control, osteotomy can be avoided.

Perinatal renal venous thrombosis: presenting renal length predicts outcome.

BACKGROUND: Renal venous thrombosis (RVT) is the most common form of venous thrombosis in neonates, causing both acute and long term kidney dysfunction. Historical predisposing factors include dehydration, maternal diabetes, and umbilical catheters, but recent reports highlight associations with prothrombotic abnormalities. STUDY: Twenty three patients with neonatal RVT were analysed over 15 years. Predisposing factors, presentation, and procoagulant status were compared with renal outcome using multilevel modelling. RESULTS: Median presentation was on day 1: 19/23 (83%) had pre/perinatal problems, including fetal distress (14), intrauterine growth retardation (five), and pre-identified renal abnormalities (two); 8/18 (44%) had procoagulant abnormalities, particularly factor V Leiden mutations (4/18). Long term abnormalities were detected in 28/34 (82%) affected kidneys; mean glomerular filtration rate was 93.6 versus 70.2 ml/min/1.73 m2 in unilateral versus bilateral cases (difference 23.4; 95% confidence interval 6.4 to 40.4; p = 0.01). No correlation was observed between procoagulant tendencies and outcome, but presenting renal length had a significant negative correlation: mean fall in estimated single kidney glomerular filtration rate was 3 ml/min/1.73 m2 (95% confidence interval 3.7 to -2.2; p = 0.001) per 1 mm increase, and kidneys larger than 6 cm at presentation never had a normal outcome. CONCLUSIONS: This subgroup of neonatal RVT would be better termed perinatal RVT to reflect antenatal and birth related antecedents. Prothrombotic defects should be considered in all patients with perinatal RVT. Kidney length at presentation correlated negatively with renal outcome. The latter, novel observation raises the question of whether larger organs should be treated more aggressively in future.

Clinical and molecular aspects of nephropathic cystinosis.

Nephropathic cystinosis, an autosomal recessively inherited lysosomal storage disease, results from impaired transport of the disulfide amino acid cystine out of cellular lysosomes. The consequent accumulation and crystallization of cystine destroys tissues, causing growth retardation in infancy, renal failure at 10 years of age, and a variety of other complications. Early oral therapy with the cystine-depleting agent cysteamine prevents renal deterioration and enhances growth. Although the lysosomal cystine carrier has been extensively studied, its molecular structure remains unknown. The lysosomal cystine transporter gene has been mapped by linkage analysis to human chromosome 17p between polymorphic microsatellite markers D17S1583 and D17S1584. Pertinent recombination events and homozygosity by descent has verified that the cystinosis gene lies in the 3.6 cM genetic interval between these two markers. The cystinosis region has been substantially reduced in size by the observation of recombination events in cystinosis patients between markers D17S1828 and D17S2167. According to radiation hybrid analysis, these two markers are separated by 10.2 cR8000 (centirad using 8000 rad radiation hybrids). Estimates of the physical size of this interval range from 187 to 510 kb. Four yeast artificial chromosomes have been identified which form a contig covering the original cystinosis region. Two P1 clones together may span the new, smaller interval, meaning that the cystinosis gene would lie on one of them. Current efforts are being directed toward using these P1 clones to isolate candidate cDNAs by a variety of methods. The ultimate cloning of the cystinosis gene will reveal how functional lysosomal porters are synthesized, targeted, processed, and integrated into the lysosomal membrane.

Cushing's syndrome with fluctuation due to adrenal adenoma.

A case of fluctuating Cushing's syndrome due to an adrenal adenoma is described. Plasma corticosteroids were frequently low and urinary steroids fluctuated markedly over a 15-month period. Only the response to dexamethasone was consistently abnormal and indicative of Cushings's syndrome.

The effect of hypopituitarism on life expectancy.

One hundred and seventy-two patients with partial or complete hypopituitarism diagnosed between 1967 and 1994 were studied retrospectively. Those with acromegaly or Cushing's disease were excluded. One hundred and two patients were male (median age at, diagnosis, 53 yr; range, 12-78 yr) and 70 female (median age at diagnosis, 51 yr; range, 1-74 yr). In 131 patients the cause of hypopituitarism was a pituitary tumor or the effects of its treatment, as the majority underwent surgery and/or radiotherapy. In 22, the cause was an extrapituitary tumor, 14 were termed idiopathic, 2 developed hypopituitarism as a result of basal sarcoid, 2 were due to trauma, and 1 was the result of Sheehan's syndrome. The patients were treated with standard replacement therapy. Mortality due to all causes was higher than expected in an age- and sex-matched control population (ratio of observed/expected deaths, 1.73; 95% confidence interval, 1.28-2.28; P < 0.01). Females tended to have a worse prognosis (ratio of observed/expected deaths, 2.29; 95% confidence interval, 1.37-3.58; P < 0.01) than their male counterparts (ratio of observed/expected deaths, 1.50; 95% confidence interval, 1.02-2.13; P < 0.01). There was a small but nonsignificant increase in the number of deaths due to vascular disease (ratio of observed/expected deaths, 1.35; 95% confidence interval, 0.84-2.07; P = 0.11). The only significant independent predictive factors for survival were age at diagnosis and hypogonadism. The majority of the male hypogonadal cohort received replacement therapy (79%), but fewer of the females did so (27%). Hypogonadal patients had a better prognosis than their eugonadal counterparts (log rank, 6.85; P < 0.01). Our data confirmed that mortality in patients with hypopituitarism is significantly increased. However, the contribution of vascular disease to this poor prognosis was not as great as previously reported, and overall, our results favor a multifactorial explanation of the poor long term outcome.

Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease.

BACKGROUND: The efficacy of allopurinol in autosomal dominant familial juvenile hyperuricaemic nephropathy (FJHN) has been disputed. AIM: To address this question, in the absence of controlled trials. DESIGN: Retrospective long-term follow-up study. METHODS: All kindreds were biochemically screened. Measurements included uric acid clearance, creatinine clearance, serum creatinine, and glomerular filtration rate (GFR). We used five siblings who had died or progressed to transplantation, ten other deceased relatives, and two index cases (one untreated, one non-compliant) as controls to assess the effects of allopurinol. RESULTS: Of eight families with FJHN, six had a strong history of renal disease and early parental death (mean age 41 years, n=10). Of 27 patients started immediately on allopurinol and treated uninterruptedly, 21 responded well, including three children born subsequently. Eight siblings (mean age 19 years) with a normal plasma creatinine at start (<120 micromol/l, mean GFR 80 ml/min/1.73 m(2)) retained stable renal function (mean 14.5 years, mean age 34 years, GFR 85 ml/min/1.73 m(2)). Of the 13 other responders, treated for up to 34 years, 10 with a creatinine <200 micromol/l at diagnosis (mean age 28 years, mean creatinine 137 micromol/l at start) now have a mean creatinine of 210 micromol/l. In contrast, five patients (mean age 26 years) with a creatinine >200 micromol/l (GFR <35 ml/min/1.73 m(2)) when allopurinol commenced, plus one untreated index case, all progressed rapidly (mean 6 years) to end-stage renal failure. In two others (one non-compliant, one initially untreated), GFR fell by >50% in 7 years. Introduction of allopurinol in the latter has stabilized GFR. DISCUSSION: Allopurinol reduced the morbidity and mortality from renal failure seen in untreated siblings and previous generations of these families. Early diagnosis of FJHN is important, so that treatment can begin before irreversible renal damage has developed.

Urinary pregnanetriol excretion in hirsutism.

Eighteen consecutive hirsute women attending an endocrine clinic have been studied by measurement of the urinary pregnanetriol excretion before and following the concurrent administration of corticotrophin and metyrapone. An abnormal increment in pregnanetriol excretion was observed in 11 of these 18 patients. It is suggested that this is evidence that an adrenal abnormality, probably operative at the 21-hydroxylase level, might be a factor responsible for the hirsutism in these 11 patients. Five adrenalectomized women who were also studied showed no significant increase in urinary pregnanetriol excretion in response to concurrent corticotrophin and metyrapone administration.

The use of an intact molecule parathyroid hormone assay in disorders of calcium metabolism.

We present the results obtained using a 1-84 human parathyroid hormone (PTH) assay in patients with abnormal calcium metabolism. A normal range was established in a series of healthy volunteers. Patients with surgically proven hyperparathyroidism (HPT) showed increased PTH levels which were separate from the normal range. Patients with probable hyperparathyroidism and milder hypercalcaemia showed a raised median PTH level but the range overlapped with normal. Patients with hypercalcaemia of malignancy showed reduced PTH levels and these patients were readily differentiated from those with probable and proven HPT by the use of the assay. In patients with chronic renal failure PTH values ranged from normal to high, the PTH concentration was found to be correlated with plasma alkaline phosphatase, but not with plasma creatinine.

Surgical treatment of children with hyperparathyroidism: single centre experience.

BACKGROUND: Hyperparathyroidism (HPT) in children is rare and surgical management is supported only by limited evidence. METHODS: Retrospective case series of all children under the age of 16 years who underwent parathyroidectomy (PTx) between 1978 and 2012. RESULTS: We identified 29 children who had surgery for HPT. Six were neonates with neonatal severe hyperparathyroidism (NSHPT) and 23 older children (age range 7-16 years) with sporadic (16) or familial (7) HPT and 93% were symptomatic. Accuracy of ultrasound and MIbi in localising solitary parathyroid adenomas was 96%, but less helpful in hyperplasia and neonates. Children with NSHPT underwent 5 curative total and 1 subtotal PTx (no reoperations). Children with familial HPT underwent 3 total and 4 subtotal PTx. One child with subtotal PTx required a reoperation. Children with sporadic HPT underwent subtotal PTx prior to 1980 (2), exploration and removal of enlarged glands 1980-2002 (5) and minimally invasive PTx since 2002 (9) and all cured by the first operation. CONCLUSIONS: Our study documents that HPT in children is predominantly symptomatic on presentation and genetically determined in 46% of cases. Imaging is accurate in localising parathyroid adenomas, but not hyperplasias. Total PTx for familial HPT was curative and minimally invasive PTx is the operation of choice for older children with sporadic HPT.

Life-threatening hypernatraemic dehydration in breastfed babies.

We describe five babies, who were exclusively breast fed, with life-threatening complications of hypernatraemic dehydration secondary to inadequate breast feeding. An increased awareness among health professionals is required so that this potentially devastating condition can be prevented.

Deafness in myxoedema.

Deafness has been demonstrated in 41 (85 per cent) of a consecutive series of 48 patients with myxoedema. There was no difference between the incidence of high and low frequency hearing loss. Severe myxoedema was associated with a higher incidence of deafness than mild myxoedema. Hearing was retested when patients were euthyroid following treatment with thyroxine. Improvement in hearing was found in 55 out of 75 deaf ears (73 per cent) and return to normal hearing occurred in 17 (23 per cent) of the 75 deaf ears.

Strychnine poisoning: clinical and toxicological observations on a non-fatal case.

The successful supportive management of an acute strychnine ingestion is described; clinical and biochemical findings are reported. A gas chromatographic assay for serum strychnine has been applied to the analysis of 19 serial blood samples. Four hours post ingestion, the serum strychnine concentration was 1.6 mg/L. This declined with T 1/2 [corrected] of 10 hours over a period of 50 hours. First order kinetics are indicated. Management of strychnine poisoning in general is discussed in the light of this case and the limited knowledge of the pharmacokinetics of the alkaloid in man.

The treatment of cystinosis with cysteamine and phosphocysteamine in the United Kingdom and Eire.

Fifty-nine patients with cystinosis were treated with cysteamine or phosphocysteamine in the United Kingdom up to May 1990. Treatment was started at a median age of 3.2 years (range 0.6-24.8 years) and continued for a median duration of 3.0 years (range 0.01-1.2 years). At the end of the study, 46 (78%) patients remained on treatment. One patient developed end-stage renal failure and 6 died. Efficacy was assessed in the 44 pre-transplant patients. The United Kingdom pre-transplant patients had significantly lower plasma creatinine concentrations at 6 and 8 years than a historical group of patients who did not receive cysteamine (P < 0.0001 and P < 0.0003, respectively). There was no significant difference between pretreatment and final post-treatment height standard deviation scores, suggesting maintenance of growth rate. The leucocyte cystine concentration was less than the accepted upper limit of the treatment range (1 nmol 1/2 cystine/mg protein) in only 21% of determinations. There was no significant difference between the mean pre-treatment and final values of leucocyte cystine concentration. The mean final doses of cysteamine (33 mg/kg per day) and phosphocysteamine (37 mg/kg per day base equivalent) were less than the mean dose (51 mg/kg per day) used in a United States multicentre trial. We conclude that cysteamine treatment was beneficial, but further improvements might be achieved by an improvement in monitoring of therapy.