Ivana Pela

Genetic Mapping to 10q23.3-q24.2, in a Large Italian Pedigree, of a New Syndrome Showing Bilateral Cataracts, Gastroesophageal Reflux, and Spastic Paraparesis with Amyotrophy

We have recently observed a large pedigree with a new rare autosomal dominant spastic paraparesis. In three subsequent generations, 13 affected individuals presented with bilateral cataracts, gastroesophageal reflux with persistent vomiting, and spastic paraparesis with amyotrophy. Bilateral cataracts occurred in all affected individuals, with the exception of one patient who presented with a chorioretinal dystrophy, whereas clinical signs of spastic paraparesis showed a variable expressivity. Using a genomewide mapping approach, we mapped the disorder to the long arm of chromosome 10 on band q23.3-q24.2, in a 12-cM chromosomal region where additional neurologic disorders have been localized. The spectrum of phenotypic manifestations in this family is reminiscent of a smaller pedigree, reported recently, confirming the possibility of a new syndrome. Finally, the anticipation of symptoms suggests that an unstable trinucleotide repeat may be responsible for the condition.

Risk factors for poor renal prognosis in children with hemolytic uremic syndrome

Many factors have been proposed as predictors of poor renal prognosis in children with hemolytic uremic syndrome (HUS), but their role is still controversial. Our aim was to detect the most reliable early predictors of poor renal prognosis to promptly identify children at major risk of bad outcome who could eventually benefit from early specific treatments, such as plasmapheresis. Prognostic factors identifiable at onset of HUS were evaluated by survival analysis and a proportional hazard model. These included age at onset, prodromal diarrhea (D), leukocyte count, central nervous system (CNS) involvement, and evidence of Shiga toxin-producing Escherichia coli (STEC) infection. Three hundred and eighty-seven HUS cases were reported; 276 were investigated for STEC infection and 189 (68%) proved positive. Age at onset, leukocyte count, and CNS involvement were not associated with the time to recovery. Absence of prodromal D and lack of evidence of STEC infection were independently associated with a poor renal prognosis; only 34% of patients D−STEC− recovered normal renal function compared with 65%–76% of D+STEC+, D+STEC− and D−STEC+ patients. In conclusion, absence of both D and evidence of STEC infection are needed to identify patients with HUS and worst prognosis, while D– but STEC+ patients have a significantly better prognosis.

Inner ear abnormalities in four patients with dRTA and SNHL: clinical and genetic heterogeneity

A significant number of patients affected by autosomal recessive primary distal renal tubular acidosis (dRTA) manifest sensorineural hearing loss (SNHL). Mutations in ATP6V1B1 are associated with early onset SNHL, whereas ATP6V0A4 mutations have been described in dRTA and late-onset SNHL. Enlarged vestibular aqueduct (EVA) was described in patients with recessive dRTA and SNHL, and recently, this abnormality has been associated with mutations in the ATP6V1B1 gene. In our study, we evaluated the presence of inner-ear abnormalities in four patients affected by dRTA and SNHL, characterized by molecular analysis. Two patients affected by severe dRTA with early onset SNHL showed the same mutation in the ATP6V1B1 gene and bilateral EVA with a different degree of severity. The other two presented similar clinical manifestations of dRTA and different mutations in the ATP6V0A4 gene: one patient, showing EVA, developed an early SNHL, whereas in the other one, the SNHL appeared in the second decade of life and the vestibular aqueduct was normal. Our study confirms the association of EVA and mutations in the ATP6V1B1 gene and demonstrates that mutations in the ATP6V0A4 gene can also be associated with EVA probably only when the SNHL has an early onset. The pathophysiology of SNHL and EVA are still to be defined.

Medullary sponge kidney associated with primary distal renal tubular acidosis and mutations of the H+-ATPase genes

BACKGROUND Medullary sponge kidney (MSK) is a rare congenital disease characterized by diffuse ectasia or dilation of precalyceal collecting tubules. Although its pathogenesis is unknown, the association with various congenital diseases suggests that it could be a developmental disorder. In addition to the typical clinical features of nephrocalcinosis and urolithiasis, patients with MSK show tubular function defects of acidification and concentration. These are considered to be secondary to morphological changes of collecting tubules. Primary distal renal tubular acidosis (dRTA) is a rare genetic disease caused by mutations in different genes involved in the secretion of H(+) ions in the intercalated cells of the collecting duct required for final excretion of fixed acids. Both autosomal dominant and autosomal recessive forms have been described, the latter is also associated with sensorineural hearing loss. METHODS AND RESULTS We report two patients presenting with dRTA, late sensorineural hearing loss and MSK, in whom molecular investigations demonstrated the presence of mutations of the H(+) proton pump ATP6V1B1 and ATP6V0A4 genes. CONCLUSIONS These observations, including a previous description of a similar case in the literature, indicate that MSK could be a consequence of the proton pump defect, thus can potentially provide new insights into the pathogenesis of MSK.

Neonatal Anuria by ACE Inhibitors during Pregnancy

Giancarlo Lavoratti, MD, Department of Pediatrics, Unit of Nephrology, Osp. A Meyer, V.L. Giordano 13, I-50135 Firenze (Italy) Dear Sir, Angiotensin-converting enzyme inhibitors (ACE-I) are effective hypotensive drugs and extensively used for the treatment of hypertension [1]. They affect both the angiotensin/aldosterone and bradykinin/prosta-glandin systems inhibiting the conversion of angiotensin I to angiotensin II, increasing circulating bradykinin levels and directly stimulating prostaglandin synthesis. These drugs are able to cross the human placenta [2, 3] and their use during pregnancy has been associated with fetal injury [4-7]. We report a case of neonatal anuria in an infant of a woman treated with ACE-I in the third trimester of pregnancy for hypertensive gestosis. This was a 36-week, 2,000 g male infant born of a 33-year-old second gravida, by cesarean section for severe oligo-hydramnios. Apgar score was 5 and 7 at 1 and 5 min respectively. The infant had growth restriction (-2 SD), hypocalvaria, profound hypotension and renal failure with no urine output. The kidneys were of normal size on renal ultrasound and the infant had no renal vasoconstriction on duplex Doppler scanning, no abnormalities of the urinary tract on the voiding cystourethrogram, no retroperitone-al/intra-abdominal masses on the abdominal computed tomography, and no cardiac dysfunctions on Doppler echocardiography. There was no history of maternal infections, but the mother had been treated for hypertensive gestosis from the 7th month of pregnancy with ACE-I (enalapril 20 mg/day) to the time of delivery. On day 3 of life, the infant was started on peritoneal dialysis. ACE activity and enalaprilat level were measured in the serum of the infant. Before dialysis, the ACE level was 7.4 μm/ml (normal 20/30). After peritoneal dialysis was started the ACE level in the serum rose to 20.5 μmol/ml. The enalaprilat level in the serum was 6.92 μg/ml, while that in the dialysate was 3.3 μg/ml. After 4 days of peritoneal dialysis the blood pressure returned to within normal limits for age. The urine output appeared on day 7 of life initially limited to 0.2 ml/kg/h, but gradually increased to 2.5 ml/kg/h. The peritoneal dialysis was interrupted on day 20 of life; a chronic renal failure remained.

The de novo Q167K mutation in the POU1F1 gene leads to combined pituitary hormone deficiency in an Italian patient.

The POU1F1 gene encodes a transcription factor that is important for the development and differentiation of the cells producing GH, prolactin, and TSH in the anterior pituitary gland. Patients with POU1F1 mutations show a combined pituitary hormone deficiency with low or absent levels of GH, prolactin, and TSH. Fourteen mutations have been reported in the POU1F1 gene up to now. These genetic lesions can be inherited either in an autosomal dominant or an autosomal recessive mode. We report on the first Italian patient, a girl, affected by combined pituitary hormone deficiency. The patient was found to be positive for congenital hypothyroidism (with low TSH levels) at neonatal screening. Substitutive therapy was started, but subsequent growth was very poor, although psychomotor development was substantially normal. Hospitalized at 10 mo she showed hypotonic crises, growth retardation, delayed bone age, and facial dysmorphism. In addition to congenital hypothyroidism, GH and prolactin deficiencies were found. Mutation DNA analysis of the patients POU1F1 gene identified the novel Q167K amino acid change at the heterozygous level. The highly conserved Q167 residue is located in the POU-specific domain. No mutation was detected in the other allele. DNA analysis in the probands parents did not identify this amino acid substitution, suggesting a de novo genetic lesion. From these data it can be hypothesized that the Q167K mutation has a dominant negative effect.

New case of thyroid dysgenesis and clinical signs of hypothyroidism in Williams syndrome

The authors report a female presenting with congenital heart defects, liver hemangiomas, and facial dysmorphisms admitted to hospital at 3 months of age because of feeding difficulties and poor growth. She had hypotonia and large tongue, “coarse” face, and umbilical hernia in presence of complex congenital cardiovascular malformations. In spite of normal neonatal screening we performed serum levels of thyroid hormones. Thyrotropin level was very high (>50 μU/ml; normal value 0.2–4 μU/ml), while serum free T3 (FT3) and free T4 (FT4) levels were normal (FT3 3.6 pg/ml, normal value 2.8–5.6 pg/ml; FT4 11.6 pg/ml, normal value 6.6–14 pg/ml); antithyroid autoantibodies were absent. Thyroid scintigraphy with sodium 99m Tc pertechnetate showed a small ectopic thyroid located in sublingual position, so treatment with L‐thyroxine 37.5 μg/24 hr was started with rapid improvement of the clinical picture. At 17 months of age the patient developed the complete characteristic phenotype of Williams syndrome (WS); the clinical diagnosis was proven by fluorescent in situ hybridization (FISH) analysis which showed hemizygous deletion of the elastin gene on chromosome 7. Recently a case of thyroid hemiagenesis in a child with WS has been reported; our patient underscores the association of hypothyroidism and WS. Moreover, our case shows that clinical manifestations of hypothyroidism may be present and the treatment may be necessary as it is in isolated congenital hypothyroidism.

Hemolytic uremic syndrome in an infant following Bordetella pertussis infection

Reported here is the case of a 6-week-old female infant with a severe Bordetella pertussis infection requiring supportive pressure-positive ventilation in the intensive care unit. After being discharged from the intensive care unit, she developed hemolytic anemia, thrombocytopenia and acute renal failure, which suggested a diagnosis of hemolytic uremic syndrome. The clinical outcome was favorable with no renal consequences. This case suggests there may be a direct cause-effect relationship between B. pertussis infection and hemolytic uremic syndrome.

Hyperammonaemia in a child with distal renal tubular acidosis.

A 5-month-old girl with distal renal tubular acidosis (RTA) and hyperammonaemia that had lasted for 12 days, despite metabolic acidosis correction, is presented in this report. The patient showed failure to thrive, poor feeding, hypotonia and vomiting crisis in absence of inborn errors of metabolism. Probably, hyperammonaemia was the result of an imbalance between the increased ammonia synthesis, in response to metabolic acidosis, and the impaired ammonia excretion, typical of distal RTA. Our case confirms that hyperammonaemia may be observed in distal RTA, mimicking an inborn error of metabolism, and it underlines that hyperammonaemia may persist several days after metabolic acidosis correction.

Lesch-Nyhan syndrome presenting with acute renal failure in a 3-day-old newborn

Acute renal failure developed during the first 3 days after birth in a newborn subsequently diagnosed with hypoxanthine-guanine-phosphoribosyl-transferase (HPRT) deficiency. Fluid infusion and allopurinol therapy normalised renal function and serum uric acid levels. Only a few cases of acute renal failure due to acute hyperuricemic nephropathy related to HPRT deficiency have previously been reported in infants, and there are no reported cases in newborns as young as 3 days old.