Growth hormone treatment in young children with Down's syndrome: effects on growth and psychomotor development

BACKGROUND—Learning disability and short stature are cardinal signs of Down''s syndrome. Insulin-like growth factor I (IGF-I), regulated by growth hormone (GH) from about 6 months of age, may be involved in brain development.
AIMS—To study long term effects of GH on linear growth and psychomotor development in young children with Down''s syndrome.
Study design—Fifteen children with Down''s syndrome were treated with GH for three years from the age of 6 to 9 months (mean, 7.4). Linear growth, psychomotor development, skeletal maturation, serum concentrations of IGF-I and its binding proteins (BPs), and cerebrospinal fluid (CSF) concentrations of IGF-II were studied.
RESULTS—The mean height of the study group increased from −1.8 to −0.8 SDS (Swedish standard) during treatment, whereas that of a Down''s syndrome control group fell from −1.7 to −2.2 SDS. Growth velocity declined after treatment stopped. Head growth did not accelerate during treatment. No significant difference in mental or gross motor development was found. The low concentrations of serum IGF-I and IGFBP-3 became normal during GH treatment.
CONCLUSIONS—GH treatment results in normal growth velocity in Down''s syndrome but does not affect head circumference or mental or gross motor development. Growth velocity declines after treatment stops.

     

Bile bilirubin pigment analysis in disorders of bilirubin metabolism in early infancy

BACKGROUND—Early and accurate diagnosis of Crigler-Najjar syndrome, which causes prolonged unconjugated hyperbilirubinaemia in infancy, is important, as orthotopic liver transplantation is the definitive treatment.
AIM—To determine whether bilirubin pigment analysis of bile in infants with prolonged unconjugated hyperbilirubinaemia provides useful diagnostic information in the first 3 months of life.
METHODS—Retrospective review of patients with prolonged unconjugated hyperbilirubinaemia referred to the liver unit, Birmingham Children''s Hospital, for the diagnosis of Crigler-Najjar syndrome. Bile bilirubin pigment composition was determined by high performance liquid chromatography. Initial diagnoses were made based on the result of bile bilirubin pigment composition. Final diagnoses were made after reviewing the clinical course, response to phenobarbitone, repeat bile bilirubin pigment composition analysis, and genetic studies.
RESULTS—Between 1992 and 1999, nine infants aged less than 3 months of age with prolonged hyperbilirubinaemia underwent bile bilirubin pigment analyses. Based on these, two children were diagnosed with Crigler-Najjar syndrome (CNS) type 1, six with CNS type 2,and one with Gilbert''s syndrome. Five children whose initial diagnosis was CNS type 2 had resolution of jaundice and normalisation of serum bilirubin after discontinuing phenobarbitone, and these cases were thought to be normal or to have Gilbert''s syndrome. One of the initial cases of CNS type 1 responded to phenobarbitone with an 80% reduction in serum bilirubin consistent with CNS type 2. In all, the diagnoses of six cases needed to be reviewed.
CONCLUSIONS—Early bile pigment analysis, performed during the first 3 months of life, often shows high levels of unconjugated bilirubin or bilirubin monoconjugates, leading to the incorrect diagnosis of both type 1 and type 2 Crigler-Najjar syndrome.

     

Thyroid dysfunction in Down's syndrome: relation to age and thyroid autoimmunity

BACKGROUND—The prevalence of thyroid disease is increased in Down''s syndrome. Most available data come from cross sectional studies.
AIMS—To study longitudinally thyroid function in patients with Down''s syndrome in Uppsala county (85 patients) up to the age of 25years.
METHODS—Observational study based on yearly follow up in a children''s clinic. Thyroid function tests were performed at each visit to the clinic.
RESULTS—Hypothyroidism was found in 30 and hyperthyroidism was found in two of the 85 patients. No sex difference was seen. Half of the patients with hypothyroidism acquired the condition before the age of 8 years, but only one of them displayed thyroid autoantibodies at diagnosis. Most patients who developed hypothyroidism after this age had thyroid autoantibodies. In the prepubertal patients with hypothyroidism, growth velocity was lower during the year before the start of thyroxine treatment than during the year after treatment began; it was also lower than that of sex and age matched euthyroidic children with Down''s syndrome.
CONCLUSION—Thyroid dysfunction in patients with Down''s syndrome is common in childhood. Consequently, annual screening is important. Autoimmune thyroid disease is uncommon in young children with Down''s syndrome but is common after 8 years of age.

     

Usefulness of antinuclear antibody testing to screen for rheumatic diseases

OBJECTIVE—To assess the usefulness of the indirect immunofluorescence antinuclear antibody test (FANA) using human laryngeal epithelial carcinoma cells as nuclear substrate, to screen for childhood rheumatic diseases.
STUDY DESIGN—A review of all FANA tests performed on children at British Columbia''s Children''s Hospital between 7 March 1991 and 31 July 1995.
RESULTS—FANA tests were positive at titres of 1:20 or greater in 41% of all subjects tested, and in 65% of all subjects in whom the diagnosis was obtained. FANA positivity occurred in 67% of those with a rheumatic disease, compared with 64% of those with a non-rheumatic disease (p=0.4). More girls had high titre FANA positivity than boys independent of whether or not they had a rheumatic disease (p=0.05). At a screening serum dilution of 1:40 a positive test has a sensitivity of only 0.63, and a positive predictive value of only 0.33 for any rheumatic disease. For systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), or overlap syndrome at a screening dilution of 1:40 the test has a very high sensitivity of 0.98, but a very low positive predictive value of only 0.10,the test having slightly better characteristics for boys than girls.
CONCLUSION—Although a negative FANA test makes a diagnosis of SLE or MCTD extremely unlikely, a positive test even at moderately high titres of 1:160 or higher is found so frequently in children without a rheumatic disease that a positive result has little or no diagnostic value. It is suggested that a screening serum dilution of 1:160 or 1:320 would increase the usefulness of the test, by decreasing false positive tests, without significantly increasing false negative tests for SLE or MCTD, and would have the potential for considerable cost savings.

     

The effect of changing attitudes to Down's syndrome in the management of complete atrioventricular septal defects

OBJECTIVES—To describe the evaluation, decision making, and care of children with a complete atrioventricular septal defect (CAVSD).
STUDY DESIGN—Retrospective study of 136 consecutive cases from 1970 to 1996.
RESULTS—A total of 115 (85%) children had Down''s syndrome. Denial of surgery without obvious medical reasons was more common in the early years, as was parental refusal of offered surgery and institutional care of the children. Improved results in later years encouraged surgical treatment for all these patients, but more liberal attitudes towards patients with Down''s syndrome preceded the improved results. The use of echocardiography as a screening method for all newborns with Down''s syndrome made it possible to plan for correction within the 1st months of life.
CONCLUSIONS—Changing attitudes in society and widespread use of echocardiography have significantly improved the management of children with a CAVSD and Down''s syndrome.
     

High incidence of Down's syndrome in infants of diabetic mothers

The incidence of Down''s syndrome was studied in 1870 infants of diabetic mothers out of 22 300 neonates born between January 1987 and April 1994 in our institution. All pregnancies were screened for diabetes and all cases of Down''s syndrome were confirmed by chromosome analysis.
Down''s syndrome (all trisomy 21) was diagnosed in 35 infants: seven were born to mothers with gestational diabetes and 28to non-diabetic mothers. The incidence of Down''s syndrome was higher in infants of diabetic mothers (3.75 per 1000 v 1.36 per 1000) (p= 0.02) with a relative risk of 2.75. No significant difference was found in maternal age between both groups (p= 0.67) and the rate of Down''s syndrome was higher in infants of diabetic mothers when compared with infants of non-diabetic mothers of similar age.
Down''s syndrome should be added to the congenital malformations already known to occur more frequently in infants of diabetic mothers.

     

Is disomic homozygosity at the APECED locus the cause of increased autoimmunity in Down's syndrome?

AIMS—To examine the age of onset of insulin dependent diabetes mellitus (IDDM) in children with Down''s syndrome compared with non-trisomic individuals, and to assess whether differences might be related to disomic homozygosity at the autoimmune polyglandular disease type 1 (APECED) gene locus.
METHODS—Children with Down''s syndrome and IDDM were identified through the Down''s syndrome association newsletter and from paediatricians. DNA was extracted from mouthbrush preparations provided by the parents and patients using standard techniques. Mapping techniques were then used to identify areas of reduction to homozygosity, including a marker that overlaps the locus for APECED. The frequency of disomic homozygosity for all markers (n = 18) was compared with a control group of 99 patients with Down''s syndrome and their parents. The families also answered a questionnaire concerning diabetes and related autoimmune conditions in the family. Details were compared with the British Paediatric Surveillance Group 1988diabetes study.
RESULTS—Children with Down''s syndrome and IDDM were diagnosed significantly earlier than the general population (6.7 v 8.0 years) with a far higher proportion diagnosed in the first 2 years of life (22% v 7%). There was no evidence of increased disomic homozygosity in the region of the APECED locus in Down''s syndrome patients with IDDM compared with simple Down''s syndrome.
CONCLUSIONS—The natural history of IDDM in Down''s syndrome is different from that of the general population. Although children with Down''s syndrome have features similar to cases of APECED, disomic homozygosity in this region does not explain the predilection for autoimmune disease.

     

Congenital central hypoventilation syndrome and Hirschsprung's disease

Five cases of the Hirschsprung''s disease-congenital central hypoventilation syndrome (CCHS) association are presented and 41 other published cases reviewed. These children have a distinct pattern of associated features, an equal sex incidence, and a characteristic spectrum of disease severity which suggests that the condition is genetically distinct from other cases of Hirschsprung''s disease. While approximately 1.5% of Hirschsprung''s disease patients, and 10% of those with total colonic aganglionosis, will have CCHS, up to 50% of CCHS patients will have Hirschsprung''s disease. Approximately 20% of CCHS/Hirschsprung patients will also have neuroblastoma or ganglioneuroma, usually multiple. Abnormalities of the eye and autonomic nervous system are also common. The ventilatory abnormality is usually evident on the first day of life. The aganglionosis is also severe, with more than half (59%) of the patients having aganglionosis extending into the small bowel.

     

Pearson's syndrome without marrow involvement

Accepted 1 April 1997
A child with a mitochondrial DNA deletion who presented with pancreatic exocrine insufficiency is reported. Though she developed many other features of Pearson''s syndrome, there was no bone marrow involvement. Syndromes associated with mitochondrial DNA defects are highly variable and absence of one feature should not inhibit investigation.

     

ARC syndrome: an expanding range of phenotypes

AIM—To describe the clinical phenotype in infants with ARC syndrome, the association of arthrogryposis, renal tubular acidosis, and cholestasis.
METHODS—The medical records for six patients with ARC syndrome were reviewed, presenting over 10 years to three paediatric referral centres.
RESULTS—All patients had the typical pattern of arthrogryposis. Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus. Although all patients had severe cholestasis, serum γ glutamyltransferase values were normal. Many of our patients showed dysmorphic features or ichthyosis. All had recurrent febrile illnesses, diarrhoea, and failed to thrive. Blood films revealed abnormally large platelets.
CONCLUSIONS—ARC syndrome exhibits notable clinical variability and may not be as rare as previously thought. The association of Fanconi syndrome, ichthyosis, dysmorphism, jaundice, and diarrhoea has previously been reported as a separate syndrome: our observations indicate that it is part of the ARC spectrum.

     

Graves' disease associated with exophthalmos,cerebral ventricular dilatation and accelerated growth

Accepted 23 September 1996
A report is presented of a girl with Graves'' disease, which was diagnosed at the age of 1.7 years. The mother had no thyroid disease. The patient developed signs of hyperthyroidism shortly before her first birthday, and the most prominent manifestations were accelerated skeletal maturation and linear growth, and dilatation of the brain ventricles. The latter manifestation, which has not been reported previously, was reversible upon normalisation of thyroid function with antithyroid treatment for three years.

     

Oesophageal atresia,VACTERL association: Fanconi's anaemia related spectrum of anomalies

Oesophageal atresia usually occurs without any genetic background. Three cases associated with Fanconi''s anaemia are reported. One neonate had growth retardation and numerous malformations including oesophageal atresia and four other components of the VACTERL association. In the two others, oesophageal atresia was isolated. In patients with such malformations an early diagnosis of Fanconi''s anaemia may have important genetic and therapeutic implications.

     

Congenital total lipodystrophy and peripheral pulmonary artery stenosis

Accepted 4 February 1997
Multiple peripheral pulmonary artery stenoses were detected in three patients with congenital generalised lipodystrophy. This association, which has not been described before, may be clinically important in patients with lipodystrophy who present with impaired exercise tolerance or heart murmurs.

     

Clinical and laboratory findings in referrals for mitochondrial DNA analysis

BACKGROUND—Increasingly, mutations of mitochondrial DNA (mtDNA) are being considered when investigating the aetiology of neurological diseases in childhood. However, they are often difficult to predict clinically.
METHOD—Mitochondrial DNA analysis was carried out on 190 children from 1992 to 1996. Most patients were screened for large scale rearrangements and point mutations at nucleotide positions 3243,3271, 8344, and 8993.
RESULTS—Mutations were found in only 15 patients (7.9%) and were either large scale rearrangements (seven patients) or point mutations at nucleotide position 3243 (eight patients). Other point mutations were screened for depending on the clinical picture. The age of symptom onset was significantly older in children with an mtDNA mutation (mean 7.0 years) compared with children without a mutation (mean 2.8 years). Neither Leigh''s syndrome (28 cases) nor severe infantile lactic acidosis (12 cases) was associated with mtDNA mutation. Only three clinical features were significantly associated with an mtDNA mutation: progressive external ophthalmoplegia, myopathy, and pigmentary retinopathy. Family history was valuable: the point mutation at nucleotide 3243 (but not the large scale rearrangements) was associated with maternal inheritance; and consanguinity was not associated with mtDNA mutations. The only investigation that provided specific evidence of an underlying mtDNA mutation was histochemical staining of muscle biopsy specimens. The large scale mutations associated with Kearns-Sayre syndrome and progressive external ophthalmoplegia were found in DNA from muscle only, not leucocyte DNA; whereas point mutations were found in leucocyte DNA.
CONCLUSIONS—Even among children seen at a neurogenetic referral centre, mtDNA mutations were very uncommon. Muscle biopsy was the only investigation to provide evidence of mtDNA abnormality.

     

Plasma free iron: a possible cause of oedema in kwashiorkor

Accepted 22 October 1996
BACKGROUND—Oedema is a sine qua non for the diagnosis of kwashiorkor yet the mechanisms leading to oedema remain ill defined.
AIMS—To relate the plasma concentration of radical promoting `free'' iron to the degree of oedema in patients with kwashiorkor.
SETTING—University teaching hospital.
PATIENTS—Fifteen children with kwashiorkor, nine of whom had severe and six of whom had a moderate degree of oedema.
METHODS—Plasma `free'' iron was measured as bleomycin detectable iron (BDI) and related to severity of oedema and plasma albumin concentration.
RESULTS—BDI was significantly higher in the patients with severe oedema (20.5 v 6.75 µmol/l) whereas the albumin concentrations were similar (16 v 17 g/l). BDI was no longer present in any patients 30 days after admission.
CONCLUSIONS—`Free'' circulating iron may contribute to the oedema of kwashiorkor, and its sequestration could hasten recovery and decrease morbidity and mortality.

     

Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome

BACKGROUND—In adults, erythema multiforme (EM) is thought to be mainly related to herpes infection and Stevens-Johnson syndrome (SJS) to drug reactions.
AIMS—To investigate this hypothesis in children, and to review our experience in the management of these patients.
METHODS—A retrospective analysis of 77 paediatric cases of EM or SJS admitted to the Children''s Hospital in Bordeaux between 1974and 1998.
RESULTS—Thirty five cases, inadequately documented or misdiagnosed mostly as urticarias or non-EM drug reactions were excluded. Among the remaining 42 patients (14 girls and 28 boys), 22 had EM (11EM minor and 11 EM major), 17 had SJS, and three had isolated mucous membrane involvement and were classified separately. Childhood EM was mostly related to herpes infection and SJS to infectious agents, especially Mycoplasma pneumoniae. Only two cases were firmly attributed to drugs (antibiotics). No patient died. EM and SJS sequelae were minor and steroids were of no overall benefit.
CONCLUSION—In paediatric practice EM is frequently misdiagnosed. The proposal that SJS is drug related in adults does not apply to children, and in our recruitment EM and SJS are mostly triggered by infectious agents. The course of both diseases, even though dramatic at onset, leads to low morbidity and mortality when appropriate symptomatic treatment is given.

     

Kimura's disease: an unusual cause of cervical tumour

Accepted 18 April 1997
An 11 year old Chinese boy developed a unilateral cervical mass associated with pronounced eosinophilia and a marked increase in IgE concentrations. A biopsy sample showed massive eosinophilic tissue infiltration consistent with Kimura''s disease. This disorder should be suspected when the clinical triad of painless unilateral cervical adenopathy, hypereosinophilia, and hyper-IgE is present, particularly in male Asian patients.

     

The prognosis of cyclical vomiting syndrome

AIMS—The medium term prognosis of cyclical vomiting syndrome (CVS) was studied to determine the proportion of affected individuals who had gone on to develop headaches fulfilling the International Headache Society criteria for migraine.
METHODS—Twenty six (76%) of 34 CVS sufferers identified from the authors'' clinical records were traced, and all agreed to participate. Each child was matched to a control, and telephone interviews were conducted using a standardised questionnaire.
RESULTS—Thirteen (50%) of the subjects had continuing CVS and/or migraine headaches while the remainder were currently asymptomatic. The prevalence of past or present migraine headaches in subjects (46%) was significantly higher than in the control population (12%).
CONCLUSION—Results support the concept that CVS is closely related to migraine.

     

Bowel function,mental health,and psychosocial function in adolescents with Hirschsprung's disease

Accepted 2 September 1996
Congenital intestinal malformations are uncommon and may pose lasting somatic difficulties. Patients with anorectal anomalies have a high frequency of persistent faecal dysfunction and psychosocial problems. This study examined whether adolescents with Hirschsprung''s disease have more psychosocial problems than their healthy peers. Nineteen adolescents (mean age 15.7 years) with Hirschsprung''s disease were assessed for bowel function, anorectal physiology, mental health, and psychosocial functioning by physical examinations, semistructured interview, and standardised questionnaires. The adolescents were compared with controls. The parents of 13 adolescents with Hirschsprung''s disease were interviewed and completed questionnaires. Thirty two per cent of the adolescents with Hirschsprung''s disease had significant impairment of continence, but no more psychopathology (16%) nor psychosocial dysfunction as a group than their healthy peers. Faecal incontinence was associated with poorer psychosocial functioning and parental criticism. The fact that a significant number of patients with Hirschsprung''s disease have incontinence into adulthood indicates the need for parental counselling, encouraging realistic expectations about continence.

     

Bladder dysfunction and neurological disability at presentation in closed spina bifida

Congenital closed spinal anomalies are associated with distortion of the spinal cord, the spinal nerve roots or both, and can result in neurological abnormalities of the lower limbs and neuropathic bladder dysfunction. This study reports clinical and videourodynamic findings in a group of 51 patients with closed spina bifida. The mean age at presentation to a specialist neurourological clinic was 3.3 years. Twenty five patients presented with urinary tract disturbance and 12 presented with neurological problems. Thirty three had normal neurological examination or only minor objective signs, 21 had normal renal tract ultrasonography but only two patients had normal videourodynamics, with 31 having two or more abnormalities during this assessment. Neither clinical neurological assessment nor the history of voiding behaviour are reliable indicators of bladder dysfunction and subsequent risk of renal damage. Therefore, all patients with a known or suspected diagnosis of closed spina bifida should have videourodynamic assessment.