Histidinaemia: screening, diagnosis, clinical picture, therapy

The paper presents the data of mass and selective screening on histidinaemia. The results of complex clinical investigation of 16 patients with histidinaemia are demonstrated. Two forms of the disease were differentiated on the basis of evaluation histidine metabolism. The results of morphological examination of liver biopsy specimens obviously demonstrated significant structural and functional disorders of the liver in histidinaemia.     

Histidinaemia: a benign metabolic disorder

Histidinaemia is a relatively common inherited metabolic disorder with an incidence similar to phenylketonuria. This paper reports the long term outcome of patients diagnosed by newborn screening in the north west of England. Between 1966 and 1990, 108 infants were diagnosed as having histidinaemia by a regional neonatal screening programme (incidence 1:11,083). A further five children were detected following diagnosis in a sibling. Of the 113, nine were lost to follow up. Infants diagnosed before 1981 (n = 47) were placed on a low histidine diet (225 mg/kg/d) for an average period of 21 months (SD 4.5). All patients were reviewed regularly, Griffiths developmental quotients (DQ) were assessed at 2 and 4 years, and WISC-R intelligence quotients (IQ) at 8, 12, and 18 years. IQ data were converted to standard deviation scores (IQ SDS) to account for increasing IQ norms with time. Neither DQ nor IQ correlated with plasma histidine at diagnosis or with the mean plasma histidine throughout life. Growth was normal in all patients. There was no apparent benefit from a low histidine diet in early childhood. In contrast to other studies, there was no excess of clinical symptoms. On the basis of these findings, histidinaemia is a benign metabolic disorder that does not require treatment.     

Histidinaemia: a benign metabolic disorder.

Histidinaemia is a relatively common inherited metabolic disorder with an incidence similar to phenylketonuria. This paper reports the long term outcome of patients diagnosed by newborn screening in the north west of England. Between 1966 and 1990, 108 infants were diagnosed as having histidinaemia by a regional neonatal screening programme (incidence 1:11,083). A further five children were detected following diagnosis in a sibling. Of the 113, nine were lost to follow up. Infants diagnosed before 1981 (n = 47) were placed on a low histidine diet (225 mg/kg/d) for an average period of 21 months (SD 4.5). All patients were reviewed regularly, Griffiths developmental quotients (DQ) were assessed at 2 and 4 years, and WISC-R intelligence quotients (IQ) at 8, 12, and 18 years. IQ data were converted to standard deviation scores (IQ SDS) to account for increasing IQ norms with time. Neither DQ nor IQ correlated with plasma histidine at diagnosis or with the mean plasma histidine throughout life. Growth was normal in all patients. There was no apparent benefit from a low histidine diet in early childhood. In contrast to other studies, there was no excess of clinical symptoms. On the basis of these findings, histidinaemia is a benign metabolic disorder that does not require treatment.     

EVALUATION OF A NATION-WIDE NEONATAL METABOLIC SCREENING PROGRAMME IN SWEDEN 1965–1979

ABSTRACT. Aim, J. and Larsson. A. (Department of Paediatrics, Karolinska Institute, St. Goran's Children's hospital, and the PKU Section, Department of Bacteriology, National Bacteriological Laboratory, Stockholm, Sweden). Evaluation of a nation-wide neonatal metabolic screening programme in Sweden 1965–1979. Acta Paediatr Scand, 70:601,.–In Sweden, neonatal screening for phenylketonuria was started in 1965 and a total of 1326000 infants were studied up to 1979. During various periods of time, screening was also carried out for galactosaemia, hereditary tyrosinaemia, histidinaemia, and homocystinuria. In screening for phenylketonuria and galactosaemia no false-negative results were obtained and the incidences were 1/30850 and 1/81100, respectively. In screening for hereditary tyrosinaemia only 1 out of 6 patients was identified by screening and the incidence was 1/106 710. Two cases of histidinaemia were detected, which corresponds to an incidence of 1/36 840. Both children developed normally without any treatment. No child with homocystinuria was detected in the screened population of more than 300 000 newborn infants. A screening programme involving phenylketonuria and galactosaemia was considered to be optimal among the tested disorders.     

Chromatographic screening of 70,328 neonates for inborn errors of amino acid metabolism

Between the years 1974 and 1984, amino acid chromatography was performed from dried blood spots and partly from urine of 70 328 neonates. Six cases of phenylketonuria, one histidinaemia, one hyperglycinaemia and three cystinurias were found. Since all these could have been detected by other methods, the regional screening was discontinued in agreement with international recommendations.     

Screening for inherited metabolic disease in Wales using urine-impregnated filter paper.

Urine specimens from 135 295 infants have been collected on filter papers and tested for 7 abnormal urinary constituents using spot tests and paper chromatography. The method has detected 5 infants with phenylketonuria, 4 with histidinaemia, 5 with cystinuria, 5 with diabetes mellitus, and one with alcaptonuria. Transient abnormalities such as tyrosyluria, generalized aminoaciduria, cystinuria, and glycosuria have been noted. 2 phenylketonuric infants failed to excrete a detectable quantity of o-hydroxyphenlacetic acid at the time of testing. The findings show that the detection of this compound in urine is an unreliable method of screening for phenylketonuria.     

Neonatal mass screening for metabolic disorders

The present situation of neonatal mass screening for metabolic disorders in eleven European countries is presented. The only disease screened for on a population wide basis in almost all countries is phenylketonuria. Screening for congenital hypothyroidism has been started in most countries or is under active consideration. A priority list of disorders that should be screened for routinely in all newborns comprises congenital hypothyroidism, hyperphenylalaninaemia, galactosaemia and maple syrup urine disease. Other disorders, like adrenogenital syndrome, cystic fibrosis. Duchenne's muscular dystrophy, histidinaemia, or tyrosinaemia cannot be recommended for mass screening at present because of an unsatisfactory test procedure or lack of effective treatment.     

Bartter syndrome in two sisters with a novel mutation of the <Emphasis Type="Italic">CLCNKB</Emphasis> gene,one with deafness

This article describes two sisters with type III Bartter syndrome (BS) due to a novel missense variant of the CLCNKB gene. The phenotypic expression of the disease was very different in these two siblings. In one sister, the disease followed a very severe course, especially in the neonatal period and as a toddler. Both the classic symptoms and the biochemical features of the syndrome were striking. In addition, she presented with sensorineural deafness, a complication yet unreported in this subtype of BS In contrast, the least affected sister was symptom free and the biochemical features of the disease although present remained discrete throughout the prolonged follow-up. It is suggested that such a difference in the phenotypic expression of the disease is possibly secondary to the modifier effect of a gene and/or results from environmental factor(s).     

Imaging of muscle disorders in children

Muscle inflammation is a relatively common pathological process in childhood. The diagnosis of the underlying cause relies on an appreciation of the pattern of clinical features, as well as the results of biochemical, histological and radiological investigations. Often the clinical and biochemical features are non-specific and insensitive. Consequently, the radiological abnormalities are very important in establishing a diagnosis and an understanding of the imaging features of muscle inflammatory disorders in childhood is needed. Some of the imaging protocols needed to investigate a variety of muscle and soft-tissue inflammatory conditions in childhood are reviewed in this article. Those features that are helpful in narrowing the differential diagnosis are indicated and a logical approach to the investigation of affected children is provided. The value of MR imaging is highlighted.     

Osteopenia of prematurity. Proposal for clinical-laboratory screening]

Osteopenia is a metabolic bone disease which affects a great deal of preterm infants. X-Ray evaluation is still the main step of the diagnostic and follow-up procedures. The Authors prospectively studied 77 newborn infants with birth weight less than 2500 grams, to identify specific clinical and biochemical features of the osteopenic infants. From the 2nd to the 12th week of life clinical, biochemical and radiological signs of osteopenia were looked for, every 2 weeks: the diagnosis of osteopenia was made on the basis of X-Ray. 26 osteopenic subjects with ga less than or equal to 32 weeks and/or bw less than or equal to 1500 grams were compared with 20 controls with ga less than or equal to 32 weeks and/or bw less than or equal to 1500 grams and with 31 control infants with ga greater than 32 weeks and bw greater than 1500 grams. Wider anterior funtanels, their progressively increasing dimensions, and craniotabe (with the "ping pong ball" sign) were the most characteristic features, as well as the increasing pattern of alkaline phosphatase activity, of the osteopenic babies. The Authors suggest a specific clinical and biochemical score to make the correct diagnosis and a non invasive follow-up in the osteopenic subjects and to avoid dangerous X-Ray exposure to babies that are not osteopenic.     

Spectrum of atypical celiac disease in North Indian children

Atypical celiac disease (ACD) presenting in childhood has rarely been documented from India. The present retrospective study analyzed features of atypical celiac disease over a 5-year period. Patients were diagnosed to have Celiac Disease (CD) as per the standard ESPGHAN criteria. The biochemical and hematological parameters of the cohort of children presenting with atypical features (ACD) were compared with children presenting as typical diarrheal CD. Twelve children were diagnosed to have CD. Seven of them presented with ACD. The two groups did not differ significantly in their age of presentation, hematological and biochemical profile. Osteoporosis as documented on bone mineral densitometry was present in all 6 patients of ACD in whom BMD was done. Short stature (4) and refractory iron deficiency anaemia (3) was the commonest modes of presentation of ACD. Occurrence of these conditions either singly or in combination warrants exclusion of celiac disease in children.     

Gastrointestinal dysmotility and pancreatic insufficiency in 2 siblings with Donohue syndrome

Donohue syndrome is a rare congenital syndrome of insulin‐resistance and abnormal glucose homeostasis, caused by mutations in the insulin receptor (INSR) gene. It is characterized by specific phenotypic and clinical features and the diagnosis is based on clinical, biochemical and genetic criteria. We report 2 siblings with Donohue syndrome (cases 1, 2) with multiple clinical and biochemical characteristics. Both patients shared the same mutation and presented with intra‐uterine growth restriction, failure to thrive, fasting hyperinsulinaemic hypoglycaemia and episodic post‐prandial hyperglycaemia. Less common clinical features were also present, such as atrial septal defect and biventricular hypertrophy, clotting disorders, abnormal liver function tests and nephrocalcinosis. Interestingly, 2 previously unrecognized manifestations of the syndrome were also identified: severe gastrointestinal dysmotility (case 1) and exocrine pancreatic insufficiency (case 2). The co‐existence of all the above clinical features makes these cases extremely rare. Gastrointestinal dysmotility should always be considered as a potentially fatal feature in patients with the syndrome, due to the complexity of the possible co‐morbidities. In addition, our clinical experience for the first time suggests that pancreatic exocrine insufficiency may offer a possible explanation for the growth retardation observed in some patients with this syndrome. Our finding that replacement treatment with pancreatic enzymes improved weight gain (case 2) implies that all patients with Donohue syndrome should be investigated for exocrine pancreatic insufficiency.     

An unusual syndrome of widened medullary cavities of the metacarpals and phalanges,aortic calcification and abnormal dentition

Two children showing the unusual features of dental dysplasia, thoracic aortic calcification, osteoporosis and radiographic changes of the hands similar to that seen in severe anemia are reported. The etiology is unknown, although both children had a history of fever of unknown origin in early infancy. There were no hematologic, genetic or biochemical abnormalities. This combination of clinical and radiographic features has not been previously reported.     

Shoshin beriberi in an infant of a thiamine-deficient mother

The classical form of thiamine deficiency in children is comprised of peripheral neuropathy, encephalopathy and high-output cardiac failure, predominantly right-sided. "Shoshin beriberi" cardiac failure has a different presentation, with vasoconstriction, hypotension and severe metabolic acidosis. A three-month breast-fed infant developed these features (biochemical tests confirmed the diagnosis). His mother, although non-symptomatic, had biochemical evidence of thiamine deficiency.     

Presentation and clinical progression of pseudohypoparathyroidism with multi-hormone resistance and Albright hereditary osteodystrophy: a case series

Anthropometric and biochemical features were retrospectively evaluated in 12 patients with pseudohypoparathyroidism, Albright hereditary osteodystrophy, and multi-hormone resistance. Hypothyroidism and subcutaneous calcifications were presenting features in younger children. Temporal trends in stimulatory hormone resistance included early thyroid-stimulating hormone elevation and progression from parathyroid hormone elevation to hyperphosphatemia and hypocalcemia.     

Steroid resistant nephrotic syndrome: role of histopathology

This study was conducted to (1) see the histopathological distribution of different subtypes in steroid resistant nephrotic syndrome (SRNS) and (2) compare the clinical, biochemical parameters and outcome between Minimal Change Disease (MCD) with non-MCD subtypes in response to immunosuppressive therapy. A retrospective analysis was done of data on all biopsy proven children with idiopathic SRNS (no response to 4 weeks of standard prednisone therapy (60 mg/m(2)/day)) referred to our institute over last 12 years. They were treated with one of the following medications: oral or intravenous cyclophosphamide, cyclosporine or combination of dexamethasone and azathioprine. A comparison was done of the demographic clinical and biochemical features different histopathologies. We studied 136 children with SRNS (100 M, 36 F). They accounted for 15.1%(136/900) of all children with idiopathic nephrotic syndrome. Focal segmental glomerulosclerosis (FSGS) was the commonest 80/136 (59%), followed by MCD (17.6%). Children with non-MCD had a significantly greater prevalence of microhematuria as compared to MCD. The other baseline clinical and biochemical features including the glomerular filtration rate (GFR) were similar. After a mean follow up of 46 (8-148) months, a significantly greater children with non-MCD 65/112) continued to be proteinuric as compared to the MCD (3/24) (p=0.0001). FSGS was the commonest cause of SRNS in our patient population. Children with SRNS secondary to MCD are more likely to achieve remission as compared to non-MCD subtypes and have a better long-term prognosis. Hence kidney biopsy is of significant prognostic value in SRNS.     

Rare multivalvular involvement in a family of scheie syndrome

A rare family of mucopolysaccharidoses—Scheie syndrome (MPS I-S) with multivalvular involvement diagnosed by clinical and radiological findings.and confirmed by biochemical features is reported. Two dimensional and doppler echocardiography were of enormous help in not only finding the valvular lesions but also their seventy.     

Two Cases of Pseudohypoparathyroidism Type Ia in Duozygotic Twins with Different Phenotypes

Pseudohypoparathyroidism (PHP) type Ia is characterized by hypocalcemia due to PTH resistance and by features of Albright’s hereditary osteodystrophy, including short stature, obesity, subcutaneous calcification and brachydactyly. A wide variety of clinical and biochemical manifestations have been reported. We report two cases of PHP type Ia in duozygotic twins with different phenotypes. The proband was a 10-yr-old girl. She showed subcutaneous ossification, shortening of the metacarpal bone, short stature, obesity and round face. She had normocalcemia (8.9 mg/dl), high-normal phosphate (5.0 mg/dl) and increased levels of serum intact PTH (152 pg/ml) and TSH (9.17 μIU/ml) levels. Her twin younger brother had atypical Albright’s hereditary osteodystrophy with only mild obesity and subcutaneous calcifications, but he showed a low level of serum calcium (7.0 mg/dl) and high levels of serum phosphate (7.6 mg/dl), intact PTH (377 pg/ml) and TSH (6.9 μIU/ml). We diagnosed them as having PHP type Ia on the basis of clinical and biochemical findings, Ellsworth-Howard test and family history. There is considerable variability in clinical and biochemical features of PHP type Ia even among affected duozygotic twins. The differences of intrauterine environment and growth history cannot account for the variable phenotypes of PHP type Ia. Even if a patient shows no AHO features, examination of all family members should be undertaken.     

Reye's syndrome in Bangalore

One hundred and twenty four cases of Reye's syndrome admitted to Vanivilas Children's Hospital, Bangalore were investigated. Clinical, biochemical and epidemiological details were obtained. The median age was five years, with no difference in sex ratio. This disease was frequent in winter months. Cases clustered in certain congested localities of the city among lower socio economic strata. Aspirin and varicella could not be associated as preceding factors. The clinical and biochemical features of the patients were suggestive of Reye's syndrome. Histopathological evaluation was done in 104 liver biopsy specimens. Virological studies for influenza and arbovirus were negative. Mortality was high (78%).     

Fulminant hepatic failure in childhood

Fulminant hepatic failure (FHF) is not an uncommon entity in pediatric age group. Although the exact incidence is difficult to assess, in our series, 25 per cent of children presenting with altered sensorium were due to FHF. The age incidence was between 4 weeks and 10 years. The overall mortality was 60 per cent. The clinical, biochemical, histopathological and prognostic features of FHF are presented in this paper. The study highlights the need for a high index of suspicion to recognise this entity when the presenting features simulate those of a central nervous system infection or Reye’s syndrome. FHF can exist with abnormal liver function tests but with a morphologically normal liver suggesting that it could be a functional syndrome.