Metabolic abnormalities in the idiopathic Fanconi syndrome: studies of carbohydrate metabolism in two patients.

Two patients with idiopathic Fanconi syndrome and glucose intolerance were studied from a metabolic perspective. They had fasting hyperglycemia, massive glucosuria, insulinopenia, ketosis, and elevated serum free fatty acids. There was a markedly blunted insulin secretory response to glucagon, tolbutamide, glucose, and arginine. One patient had the findings of diabetic retinopathy and a sensory neuropathy. Neither patient could convert galactose to glucose, but they did not have galactosemia. As a result of these studies, and previous reports in which similar changes were noted, we conclude that diabetes mellitus may occur in patients who have had idiopathic Fanconi syndrome for many years.

Reduced platelet aggregation in hemolytic-uremic syndrome.

Platelet aggregation was studied in three patients during the course of the hemolytic-uremic syndrome (HUS) when the platelet count was below 100,000/mm3 and after the platelet count had normalized. Platelet aggregation was examined in response to epinephrine, adenosine diphosphate (ADP) and collagen. Aggregation did not occur in response to epinephrine when the patients were thrombocytopenic but normal tracings were obtained when the platelet counts had returned to normal. In contrast, platelet-rich plasma from normal subjects diluted with platelet-poor plasma from patients to comparable platelet counts, showed normal aggregation responses. This study demonstrates that platelet aggregation is reduced in the early phase of the HUS.

Renal dysplasia associated with in utero exposure to gentamicin and corticosteroids.

We report on a patient with renal cystic dysplasia, whose mother was given gentamicin and corticosteroids early in pregnancy. We speculate that these drugs may be implicated in abnormal nephrogenesis in humans. This speculation is based on gentamicin-induced small kidneys (oligonephronia) in the rat. Renal cystic disease has been demonstrated following glucocorticoid administration early in gestation. We realize that there is no proof for a casual relationship between gentamicin and/or glucocorticoids in the pathogenesis of this patient's renal disease. However, it is possible that renal cystic dysplasia in humans is not solely the result of a genetic defect.

Postaxial polydactyly, ulnar ray dysgenesis, and renal cystic dysplasia in sibs.

We describe two brothers with variable expression of a unique syndrome. One sib has postaxial polydactyly of the right hand and feet, two digits on the left hand (a thumb and first digit), bilateral ulnar ray dysgenesis, ectrodactyly of one hand, and ultrasonic evidence of cystic kidneys. His brother has postaxial polydactyly and small kidneys. The parents and a third sib are normal. They do not have the Pallister ulnar-mammary syndrome but may have an unusual form of the Weyers oligodactyly syndrome. This appears to be the first report of an acro-renal syndrome with ulnar dysgenesis, oligodactyly, polydactyly, and dysplastic kidneys.

Galloway-Mowat syndrome of abnormal gyral patterns and glomerulopathy.

The combination of microcephaly, gyral abnormalities, developmental delay, and a glomerulopathy constitutes a recognizable syndrome. The inheritance is autosomal recessive. Additional abnormalities may include seizures, minor facial anomalies, and hiatal hernia. Onset of proteinuria often occurs in the first 3 months of life, but always before age 3 years. A uniform pattern of renal histologic changes has not been found. There is no effective treatment for the neurologic or renal manifestations of this condition. The prognosis is extremely poor; every patient but one has died before age 5 1/2 years. Antenatal diagnosis may be possible.

Nephrotic syndrome, microcephaly, and developmental delay: three separate syndromes.

We describe a patient with microcephaly, developmental delay, and nephrotic syndrome who had normal renal function and normal brain imaging studies. She does not have the Galloway-Mowat syndrome. The concurrence of nephrotic syndrome with microcephaly and developmental delay may be coincidental, or may reflect one of at least three syndromes: Galloway-Mowat, a second syndrome of microcephaly, nephrotic syndrome and developmental delay (MNSDD), and a third syndrome of microcephaly, developmental delay, and spondylorhizomelic short stature.

Cystic kidneys associated with connective tissue disorders.

Advances in molecular genetics have resulted in the identification of several forms of autosomal dominant polycystic kidney disease (PKD). Cystic kidneys have also been observed in tuberous sclerosis, von Hippel-Lindau syndrome, oro-facial-digital type I syndrome, Hajdu-Cheney syndrome, Ehlers-Danlos syndrome, and an "overlap" connective tissue disorder, and cannot be distinguished by ultrasonography from PKD. We have studied four children with similar cystic kidneys. None had a family history of PKD. One child has osteogenesis imperfecta type IV, two appeared to have a mild Ehlers-Danlos syndrome, and the fourth has inguinal hernias and undescended testes. We speculate that polycystic kidneys may occur in connective tissue dysplasias. We also realize that these may be chance associations with spontaneous mutations for PKD.

Familial hypoplastic glomerulocystic kidney disease: a definite entity with dominant inheritance.

Autosomal dominant (or possibly X-linked) inheritance of familial hypoplastic glomerulocystic kidneys is described in a mother and son who both had stable, chronic renal failure, cystic kidneys by ultrasound examination, glomerular cysts as demonstrated histologically, and malformed renal calyces. There was no evidence of other congenital abnormalities apart from prognathism, small stature and pyloric stenosis. Hepatic fibrosis was not evident in a liver biopsy specimen. These findings add further confirmation to the existence of the syndrome of familial hypoplastic glomerulocystic kidney disease with dominant inheritance.

Renal dysgenesis in a monozygotic twin: association with in utero exposure to indomethacin.

We report oligohydramnios and renal dysgenesis in one of identical twins, which might have resulted from in utero exposure to early, prolonged high-dose indomethacin. The proposita was the second of twin girls born at 36 weeks of gestation. Pregnancy was complicated initially by polyhydramnios in both amniotic sacs and premature uterine contractions. After administration of indomethacin and terbutaline from 16 to 30 weeks' gestation, serial prenatal ultrasound examinations ultimately showed oligohydramnios in twin B and resolution of polyhydramnios in twin A. On day 5 twin B developed hematuria, hypertension, renal failure, hyponatremia, hyperkalemia, metabolic acidosis, sodium wasting and severe, transient inability to excrete potassium. Renal sonography showed enlarged, hyperechoic kidneys with almost no corticomedullary differentiation. Renal biopsy revealed immature glomeruli, dilated Bowman's spaces, dilated tubules, and interstitial fibrosis. The liver was histologically normal. Indomethacin may induce oligohydramnios and transient renal insufficiency in humans and renal dysgenesis in fetal monkeys; it might have induced the abnormalities in this patient.

Variable expression of autosomal recessive polycystic kidney disease and congenital hepatic fibrosis within a family.

Blyth and Ockenden [1971] assigned patients with autosomal recessive polycystic kidney disease (ARPCKD) to 4 discrete groups (perinatal, neonatal, infantile, juvenile) on the basis of the age of presentation. They and others speculated that at least 4 genes were responsible for what they considered to be closely related, but different conditions. These views have gained wide but not universal acceptance. Some workers have insisted that the perinatal and neonatal "forms" of ARPCKD differ fundamentally from the juvenile "form." However, others have proposed that ARPCKD-CHF (congenital hepatic fibrosis) and CHF-ARPCKD are manifestations of the same disease with variation of expression in a kindred. We report on a patient who presented at birth (1979) with ARPCKD and respiratory distress. He died at 18 hr. An older sib presented at 16 yr in 1984. She had no symptoms, but her mother wanted reassurance that the daughter did not have a condition similar to that of the deceased sib. Blood pressure was 120/80 mm Hg and there was hepatosplenomegaly. A diagnosis of renal tubular ectasia and CHF was made by ultrasonography, radiologic studies, and a liver biopsy. The evidence from families such as this favors the concept that ARPCKD and CHF presenting as Blyth and Ockenden's perinatal form, and CHF and renal tubular ectasia as their juvenile form, are manifestations of the same genetic disorder, and that the different manifestations are more likely variations in expression than the results of different mutant genes. The manifestations in this family add weight to the growing body of evidence that intrafamilial variability may occur, not only in autosomal dominant conditions, but also in autosomal recessive disorders.

Cystic kidney disease in Hajdu-Cheney syndrome.

We report on 2 unrelated patients with Hajdu-Cheney acroosteolysis syndrome, who had cystic kidneys with ultrasonographic changes similar to those of autosomal dominant polycystic kidney disease. Neither had a family history of Hajdu-Cheney syndrome or polycystic kidneys, nor manifestations of any other syndrome. On the basis of the findings in these 2 patients and a review of published cases, we suggest that cystic kidneys are an important component of Hajdu-Cheney syndrome.

Further evidence that the Hajdu-Cheney syndrome and the "serpentine fibula-polycystic kidney syndrome" are a single entity.

The Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant disorder. It comprises a coarse face, short neck, hirsutism, joint laxity, and normal intelligence. Bone dysplasias, include acro-osteolysis, bathrocephaly, and vertebral anomalies. In 1988, Exner [1988: Eur J Pediatr 147:544-546] coined the term "serpentine fibula-polycystic kidney syndrome" (SFPKS) when he reported on a girl with short stature, unusual facial appearance, polycystic kidneys, and elongated curved fibulae. He postulated that it was a new entity different from the Melnick-Needles syndrome. Since his report, five similar cases have been published. Similarities between both HCS and SFPKS were noticed first by us and then by other authors. In this report we show that many clinical and radiological characteristics are shared by the HCS and the SFPKS and hypothesize that they represent a single entity with a variable degree of expression.

Autosomal dominant inheritance of small kidneys.

We report herein bilateral small kidneys found in a mother and her two sons. This was associated with slowly progressive chronic renal failure. None of the patients had any of the associated clinical manifestations of recognized syndromes in which there is autosomal dominant inheritance of bilateral small kidneys (e.g., branchio-oto-renal syndrome). Nor did they have the clinical symptoms commonly associated with medullary cystic kidney-juvenile nephronophthisis. However, there were some manifestations that have been reported in familial hypoplastic kidneys with glomerular cysts. Without wanting to claim that this is a "new" syndrome, we are, however, unaware of any reports describing a similar kindred. The importance of this report stems mainly from the fact that a woman with mild to moderate stable chronic renal failure associated with, or caused by, bilateral small dysplastic kidneys gave birth to two sons with the same problem.

Infundibulopelvic stenosis, multicystic kidney, and calyectasis in a kindred: clinical observations and genetic analysis.

Congenital obstructive anomalies of the urinary tract usually occur sporadically. We describe inheritance in a three-generation kindred of a spectrum of kidney anomalies consistent with an autosomal-dominant mode of transmission, with incomplete penetrance, calyectasis (maternal grandmother), infundibulopelvic stenosis (uncle), and multicystic kidney (male proband, age 4 years). The proband's mother, father and half sister had normal renal imaging studies. Inheritance of informative polymorphic markers (3'-HVR, GGG1, GGG9, SM-7, KG8, and CW3) mapping close to the adult polycystic kidney disease type 1 (PKD-1) and tuberous sclerosis (TSC-2) loci on chromosome 16p was evaluated by Southern blot studies and by PCR-based, fluorescent genotyping for linkage to phenotype. The 3 affected individuals, as well as the unaffected mother (obligate carrier) and unaffected half-sister, inherit a common chromosome haplotype linked to the PKD1 locus. Our findings support the hypothesis that these anomalies may be part of a spectrum of obstructive renal dysplasia which are inherited as a simple Mendelian trait exhibiting an autosomal-dominant mode of transmission with variable expression and incomplete penetrance.

Elevated serum elastase and alpha-1-antitrypsin levels in hemolytic uremic syndrome.

Clinical observations and experimental studies have pointed to a role for leukocytes in the pathogenesis of the typical or epidemic form of the hemolytic uremic syndrome. As a result of these observations we measured serum elastase levels and the levels of two protease inhibitors, alpha-1-antitrypsin and alpha-2-macroglobulin in 12 patients with this syndrome. The serum elastase levels were significantly elevated in patients compared with normal individuals (421 +/- 278 vs 91 +/- 27 mg/dl, p less than 0.005) and patients with renal diseases not caused by hemolytic uremic syndrome (191 +/- 254 mg/dl, p less than 0.025). The serum alpha-1-antitrypsin levels were also significantly elevated: hemolytic uremic syndrome vs normals (774 +/- 260 vs 285 +/- 98 ng/ml, p less than 0.0001); and in hemolytic syndrome compared with patients with renal diseases not caused by hemolytic uremic syndrome (774 +/- 260 vs 335 +/- 131 ng/ml, p less than 0.0001). There were no significant differences in the alpha-2-macroglobulin levels among the three groups. There was a significant correlation between the serum elastase levels and the total white cell counts as well as between the elastase and the polymorphonuclear cell counts but not among any of these values and the serum creatinine concentrations. These results provide additional evidence favoring the possibility that leukocytes are activated in patients with hemolytic uremic syndrome.

Reduced red blood cell carbonic anhydrase activity in a patient with nephrolithiasis.

Low levels of red blood cell (RBC) carbonic anhydrase (CA) activity in hemoglobin-free hemolyzate (HFH) were found in 2 children with nephrolithiasis when compared to age-matched controls. The lowest levels were consistently found over a two year period in a 6 1/2 year old boy (U.P.) whose renal calculi contained uric acid, ammonia, calcium carbonate and oxalate. His RBC CA values ranged from 1.4-2.7 U/g Hb compared with levels of 3.9-5.3 U/g Hb in control subjects. Statistical comparisons of the mean values for U.P., 2.06 U/g Hb, and his age-matched control subjects, 4.46 U/g Hb, revealed a significant difference (P = less than 0.001). Similar reductions in RBC CA activity were found in his father--2.0 and 2.1 U/g Hb compared with 3.3 and 3.9 U/g Hb in adult controls. HFH CA activity was not decreased in the mother or sister. Polyacrylamide gel electrophoresis of HFH from 4 of the children and the father of U.P. was abnormal. However, this abnormal electrophoretic pattern could only be demonstrated when the gel was run for 120 minutes and not when it was run for 80 or 160 minutes. We have identified a patient and his father with low levels of RBC CA activity.

Ultrastructural changes in the glomerular basement membrane of patients with Laurence-Moon-Biedl-Bardet syndrome.

Renal disease, although not a cardinal feature of the Laurence-Moon-Biedl-Bardet syndrome (LMBBS), occurs in more than 70% of patients and is an important cause of morbidity and mortality. Renal ultrastructural changes have not been well delineated. We have studied glomeruli from three patients with LMBBS and have found similar ultrastructural changes in glomerular basement membrane (GBM). Two patients had decreased renal function, hypertension, and markedly abnormal intravenous urograms with reduced concentration of dye and abnormal pelvicalyceal systems; one patient had normal renal function and minimal distortion of the pelvicalyceal system of one kidney. Ligh microscopy revealed varying degrees of increase in mesangial cellularity and matrix. These changes involved almost all glomeruli and were segmental. The abnormalities ranged from mild mesangial cell proliferation to complete sclerosis of the glomerular tuft. Ultrastructural study revealed marked alterations of the glomerular basement membrane: effacement of the trilaminar architecture, segmental and irregular thickening alternating with thinning and rarefaction, accumulation of granular and fibrillary material within the inner third of the GBM. These ultrastructural changes may be the earliest and primary glomerular abnormality seen in LMBBS because they were seen in a patient who had minimal changes on light microscopy.

Pseudohypoaldosteronism.

Three children, two of whom were siblings, had pseudohypoaldosteronism. The features of this condition include failure to thrive, hyperkalemia, metabolic acidosis, salt wasting, elevated peripheral renin activity, and increased plasma aldosterone concentration. Hyperplasia of juxtaglomerular apparatus was seen in a renal biopsy specimen from one of these patients. Administration of large quantities of salt normalized the serum electrolyte abnormalities and permitted normal growth. Furthermore, the serum electrolyte abnormalities were prevented by administration of increased amounts of salt to one of these children from birth.

Red cell membrane phospholipid abnormalities in the hemolytic uremic syndrome.

Eight patients with the hemolytic uremic syndrome had depression of percentage of red cell phosphatidyl ethanolamine content. Five patients also had subnormal plasma tocopherol levels. In addition all patients had significant increases in total plasma lipids which could contribute to peroxidative damage. The association of depressed red cell phosphatidyl ethanolamine and plasma tocopherol levels is suggestive of peroxidative damage, and may contribute to the hemolysis in this syndrome.

Friedreich's ataxia with nephrotic syndrome and convulsive disorder: clinical and neurophysiological studies with renal and nerve biopsies and an autopsy.

In a sibship of four, Friedreich's ataxia and minimal lesion nephrotic syndrome occurred in two siblings, a third sibling had Friedreich's ataxia, but no evidence of nephrotic syndrome; the fourth sibling had neither condition. The chance of Freidreich's ataxia and minimal lesion nephrotic syndrome occurring in two siblings is small, and suggested a common immunological abnormality. High dose prednisone and antimetabolites given for the nephrotic syndrome did not appear to affect the course of Friedreich's ataxia. The two siblings with Friedrich's ataxia and nephrotic syndrome developed epilepsy at age 15 years. All three children with Friedreich's ataxia had abnormal electroencephalograms (EEGs). These epileptiform EEG abnormalities were probably inherited from the mother, who had spike wave epilepsy. The neurologic deficits of Friedreich's ataxia, in turn, may have allowed the EEG trait to be expressed as a seizure disorder. The progressive ataxia and epileptic, sometimes myoclonic, seizures in these patients and the dentate nucleus changes in the autopsied patient were consistent with the diagnosis of dyssynergia cerebellaris myoclonica. This suggested that the latter disorder may represent a coincidence of two genetic entities: Friedreich's ataxia and spike wave epilepsy.