Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness.

H+-ATPases are ubiquitous in nature; V-ATPases pump protons against an electrochemical gradient, whereas F-ATPases reverse the process, synthesizing ATP. We demonstrate here that mutations in ATP6B1, encoding the B-subunit of the apical proton pump mediating distal nephron acid secretion, cause distal renal tubular acidosis, a condition characterized by impaired renal acid secretion resulting in metabolic acidosis. Patients with ATP6B1 mutations also have sensorineural hearing loss; consistent with this finding, we demonstrate expression of ATP6B1 in cochlea and endolymphatic sac. Our data, together with the known requirement for active proton secretion to maintain proper endolymph pH, implicate ATP6B1 in endolymph pH homeostasis and in normal auditory function. ATP6B1 is the first member of the H+-ATPase gene family in which mutations are shown to cause human disease.

A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis.

The rare bone thickening disease osteopetrosis occurs in various forms, one of which is accompanied by renal tubular acidosis (RTA), and is known as Guibaud-Vainsel syndrome or marble brain disease. Clinical manifestations of this autosomal recessive syndrome comprise increased bone density, growth failure, intracerebral calcification, facial dysmorphism, mental retardation, and conductive hearing impairment. The most common cause is carbonic anhydrase II (CAII) deficiency. Several different loss of function mutations in CA2, the gene encoding CAII, have been described. To date, there have been no exceptions to the finding of CAII deficiency in patients with coexistent osteopetrosis and RTA. Most often, the RTA is of mixed proximal and distal type, but kindreds are reported in which either distal or proximal RTA predominates. We report the molecular genetic investigation of two consanguineous kindreds where osteopetrosis and distal RTA (dRTA) were both manifest. One kindred harbours a novel homozygous frameshift alteration in CA2. In the other, CAII levels were normal despite a similar clinical picture, and we excluded defects in CA2. In this kindred, two separate recessive disorders are penetrant, each affecting a different, tissue specific subunit of the vacuolar proton pump (H(+)-ATPase), providing a highly unusual, novel genetic explanation for the coexistence of osteopetrosis and dRTA. The osteopetrosis is the result of a homozygous deletion in TCIRG1, which encodes an osteoclast specific isoform of subunit a of the H(+)-ATPase, while the dRTA is associated with a homozygous mutation in ATP6V1B1, encoding the kidney specific B1 subunit of H(+)-ATPase. This kindred is exceptional firstly because the coinheritance of two rare recessive disorders has created a phenocopy of CAII deficiency, and secondly because these disorders affect two different subunits of the H(+)-ATPase that have opposite effects on bone density, but which have only recently been determined to possess tissue specific isoforms.

Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss.

Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively. We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in "sporadic" cases. The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.

Microscopic nephrocalcinosis and hypercalciuria in nephrotic syndrome.

Focal calcification is an occasional tubular abnormality seen in minimal-change nephrotic syndrome. Nephrocalcinosis was also reported in premature infants as a consequence of hypercalciuria resulting from long-term furosemide therapy. We describe 4 nephrotic children (3 minimal change, 1 diffuse proliferative glomerulonephritis) with transient hypercalciuria and intraluminal calcifications in renal histopathological specimens without radiologic evidence of renal calcification. These children were resistant to corticosteroid therapy and were receiving furosemide therapy along with albumin for management of oedema. Two of the children also had urinary infection. We were concerned that children with nephrotic syndrome are at risk for nephrocalcinosis, and urinary calcium and pH should be monitored carefully during prolonged furosemide use, especially in children with nephrotic syndrome with reduced initial responsiveness to corticosteroid therapy. HUM PATHOL 31:1363:1367.

Peritonitis in children on continuous ambulatory peritoneal dialysis.

Between 1979 and 1985, 26 patients on continuous ambulatory peritoneal dialysis had 97 episodes of peritonitis. These occurred over a period of 336 patient months, giving an incidence of one episode every 3.5 patient months. The micro-organisms comprised Gram-positive and Gram-negative bacteria as well as fungi which accounted for six episodes. Gram-positive bacteria were isolated in 49 of the 97 episodes (50.5%) with Staphylococcus epidermidis predominating. The incidence of culture-negative peritonitis was high (27.8%). Because of failure to respond to treatment, or because of frequent recurrences, 42% patients were transferred to haemodialysis. The changing bacterial ecology has necessitated an alteration in choice of antibiotics. Cefamandole and/or gentamicin are no longer appropriate since 46% strains of S. epidermidis are now methicillin-resistant. Our 'best guess' choice for bacterial peritonitis would now start with netilmicin, vancomycin being added if indicated. For fungal peritonitis we would now start with a primary course of anti-fungal agents followed by early removal of the catheter if there is no response to treatment.

Kasabach-Merrit syndrome in infants.

METHODS: Four infants with Kasabach-Merrit syndrome syndrome have been treated at the University Hospital, Trabzon. They had large varied-site cutaneous hemangiomas. Diagnosis was performed with clinical and laboratory studies. All patients has severe thrombocytopenia and anemia. Fibrinogen and fibrin split products were examined in two patients and lower fibrinogen and over fibrin split products levels were detected in them. All patients were admitted to the intensive care unit and they were treated with antibiotics, fresh blood transfusion and thrombocyte suspension. Two out of four patients were previously treated with steroids unsuccessfully and one patient died due to disseminated intravascular coagulopathy. Three patients were treated with interferon alfa-2a and compression. RESULTS: In two patients the lesions regressed 60-80% following the five months therapy and in the other patient the lesion was completely excised after one month therapy. CONCLUSIONS: Interferon alfa-2a and compression were found to be remarkably effective in the treatment of Kasabach-Merrit syndrome.

Postpartum hemolytic uremic syndrome with a more severe liver involvement.

A 22-year-old woman presented with postpartum hemolytic uremic syndrome with a more severe hepatic involvement. The patient was dialysed and successfully treated with plasma infusion and intravenous immunoglobulin. Two months following discharge her creatinine clearance was 105 ml/min/1.73 m2, 99mTc DTPA scan and brain CT were normal. Here child is also alive and healthy.

Serial quantitative 99mTc DTPA imaging in CMV-associated renal allograft dysfunction.

Two cases of cytomegalovirus associated renal allograft dysfunction were monitored by serial 99mTc DTPA imaging and cytomegalovirus specific fluorescent antibody tests. One case of primary cytomegalovirus disease associated with pneumonitis, hepatitis and pyrexia occurred 25 days after transplantation. The second case, due to cytomegalovirus reactivation/reinfection had fewer symptoms and occurred 78 days following transplantation. 99mTc DTPA perfusion index at the height of the cytomegalovirus associated illness remained unaltered in both cases, and did not suggest the presence of acute rejection. This non-reactive response was associated with a rapid return of graft function. The combined use of these rapid diagnostic tests during suspected rejection episodes may be useful in indicating cytomegalovirus associated allograft dysfunction and preventing the addition of further potentially harmful immunosuppressants.

Management of rachitic deformities in children with chronic renal failure.

Five children with chronic renal failure and severe rachitic deformities of the lower limbs were treated with 1 alpha-hydroxyvitamin D (1 alpha-OHD3) for 16 to 53 months. There was symptomatic, biochemical and radiological improvement in all five children and operative correction of their deformities was not needed. We recommend a trial of treatment with 1 alpha-OHD3 for this condition before surgical procedures.

Fatal polyarteritis nodosa with massive mesenteric necrosis in a child.

Polyarteritis nodosa (PAN) is a rare vasculitic syndrome in childhood. There are few reported cases of ischaemic necrosis of the intestine and even fewer survivors in adults. We report the case of a 10-year-old boy with PAN and an acute abdomen that required operative intervention. Evidence was found of mesenteric arteritis with large ischaemic segments resulting in infarction and perforation.

A rare case of truncal duplication.

A rare case of truncal duplication is presented in which the infant had an extra truncus with well-formed extremities, a hypoplastic thorax, and a small abdomen. The truncus was attached to the infant from the thorax to the umbilicus. Successful separation of the truncus and reconstruction of the thoracoabdominal wall defect were performed in the neonatal period.

Roberts SC phocomelia with isolated cleft palate, thrombocytopenia, and eosinophilia.

The Roberts-SC (Pseudothalidomide) syndrome is a rare autosomal recessive disorder. We present a Roberts-SC Syndrome in a 20-day-old girl with phocomelia of the upper limbs, isolated cleft palate, micrognathia, prominent eyes, pectus excavatum, and pes equinovarus. Peripheral blood smear revealed thrombocytopenia and hypereosinophilia. Premature centromere separation in the child and also in her normal mother was noted.

Pyknodysostosis: hemangioma of the skull as a new finding.

Pyknodysostosis is a rare sclerosing bone dysplasia syndrome with autosomal recessive inheritance. Here, we report a case of pyknodysostosis, with characteristic physical and radiological findings, but also with a hemangioma of the skull, as a non reported finding sofar.

Campomelic dysplasia associated with mandibular clefting.

Campomelic dysplasia (CD), is a lethal dwarfism of the newborn, characterised by rhizomelic dwarfism, bowed femora and tibiae, associated with other skeletal and extraskeletal defects. It is suggested that there are long-limbed and short-limbed varieties. Various clinical and radiological anomalies have been described in both types of CD. Here, we describe for the first time a cleft in the mandibula in a patient with campomelic dysplasia.

Aicardi syndrome: a variant example with new clinical findings.

Aicardi syndrome, which shows X-linked dominant inheritance, is characterized by corpus callosum agenesis, infantile spasms, chorioretinitis, chorioretinal lacunae, psychomotor retardation, microphthalmy, cerebral atrophy and vertebral abnormalities. A 3/12 year-old girl with Aicardi syndrome who has dilated right lateral ventricle and leucomalacy in the right frontal lobe on magnetic resonance imaging (MRI) is presented. As far as we know, this combination of symptoms was not described previously in the literature.

Multiple vertebral segmentation defects. Brief report of three patients and nosological considerations.

Multiple vertebral segmentation defects i.e. multiple malformations of vertebrae and ribs are characterized by short neck, scoliosis, short trunk and deformity of the ribcage. There are three major subtypes; Jarcho-Levin syndrome, spondylothoracic dysostosis and spondylocostal dysostosis, with different inheritance patterns, survival rates and associated malformations. We describe three cases of multiple vertebral segmentation defects, two with familial spondylothoracic dysostosis and one with sporadic spondylothoracic dysostosis, and anomalies i.e. super-numerary breast, clubfeet deformity, myelomeningocele, intradural lipoma, and Arnold-Chiari malformation.

Hydrocephalus, corneal opacities, deafness, left ventricle hypertrophy, clinodactyly in an adolescent patient. A new syndrome associated with glucocerebrosidase deficiency.

We report a 12-year-old girl with an unusual phenotype of Gaucher disease type 3. Liver glucocerebrosidase activity was 20% of the normal. In addition to common manifestations such as hepatomegaly, she showed primary communicating hydrocephalus, corneal opacities, deafness, left ventricle hypertrophy, and clinodactyly of hands and feet. We suspect cardiomyopathy to be due to myocardiac infiltration with Gaucher cells, and corneal opacities to result from an accumulation of lipid-like inclusions into the posterior stromal keratinocytes. We were only able to find one previously published sibship disclosing similar features, which could allow the delineation of a new clinical variant of Gaucher disease.

A new treatment with bleomycin for complicated cutaneous hemangioma in children.

Cutaneous hemangiomas are the most common tumors of infants and children. Although they frequently resolve spontaneously, approximately 5% produce complications such as bleeding, infection, consumption coagulopathy and unesthetic appearance. Various methods of treatment are described for these complicated hemangiomas. We used a new type of treatment for complicated cutaneous hemangiomas as intralesional bleomycin (BLM) injection, for the first time in the literature. This agent produced extensive fibrosis and spontaneous resolution of hemangiomas. Fourteen patients with complicated hemangiomas (twelve capillary and two cavernous) have been treated with this method during a three-years period. Of these fourteen patients, five had bleeding, three had infection, one had ulceration, and five had unesthetic appearance and continued rapid growth. Lesions of three patients were completely excised after only one BLM injection. In the other eleven patients lesions regressed 60-100% during 6-14 months with two to three BLM injections. We believe that intralesional BLM injection is simple, and very useful for treatment of complicated cutaneous hemangiomas.

The effect of ATP-MgCl2 on lipid peroxidation in ischemic and reperfused rabbit kidney.

Oxygen metabolites formed during reperfusion of ischemic kidneys prevent recovery of renal function after short periods of renal ischemia. The administration of ATP-MgCl2 is beneficial to the survival of animals after hemorrhagic shock, severe burns, septicemia-peritonitis, post-ischemic hepatic failure, bowel ischemia, and endotoxic shock. In this study, the effect of ATP-MgCl2 on lipid peroxidation and its curative effect were evaluated by measuring the decomposition products of lipid peroxidation, detected as thiobarbituric-acid reactive substances in homogenized kidney tissues in ischemic and reperfused rabbit kidneys. Ischemia was performed by clamping the right renal artery for 60 minutes followed by 30 minutes of reperfusion. Thirty-six rabbits were classified into 6 groups containing 6 rabbits in each. In the first group, no renal ischemia-reperfusion (I-R) was designed (Sham group), the right kidney was removed 90 minutes later. In the second group, I-R was established but nothing given. Saline 0.25 cc/kg was given into the right renal artery in group 3 two minutes before ischemia, and in group 4 two minutes before reperfusion. ATP-MgCl2 17.5 mumol/kg (0.25 cc/kg) was given two minutes before ischemia in group 5, and before reperfusion in group 6. The right kidneys of the rabbits were removed and thiobarbituric-acid reactive substances in the homogenates were measured. In addition, histopathological evaluation was performed. High lipid peroxidation products were recorded in groups 2-5, whereas in group 6, these levels were low similar to those obtained in Sham group (76.72 +/- 1.01 nmol/g tissue). On histopathological evaluation, a considerable cell damage resulting from I-R trauma especially in proximal tubules was observed. In groups which were under saline effect, no histopathological damage was found. Histophatological preservation was better in group 6 rather than in group 5. The results of this study indicate that ATP-MgCl2 is remarkably effective for preventing the lipid peroxidation if given before reperfusion but not before ischemia in experimental I-R injury in rabbit kidneys.

Asymmetric crying facies: an index of other malformations.

Congenital hypoplasia or absence of the depressor anguli oris muscle is a minor congenital anomaly causing asymmetrical crying facies (ACF). The interesting aspect of this abnormality lies in the frequently associated abnormalities. Cardiac, urogenital, musculoskeletal, respiratory and cervicofacial defects have been described in cases with ACF. Therefore it is suggested that ACF can be used as an index of other congenital malformations. We report three cases with ACF who had varied congenital anormalites.