Microdeletions including FMR1 in three female patients with intellectual disability - further delineation of the phenotype and expression studies.

Fragile X syndrome (FXS) is one of the most common causes of intellectual disability/developmental delay (ID/DD), especially in males. It is caused most often by CGG trinucleotide repeat expansions, and less frequently by point mutations and partial or full deletions of the FMR1 gene. The wide clinical spectrum of affected females partly depends on their X-inactivation status. Only few female ID/DD patients with microdeletions including FMR1 have been reported. We describe 3 female patients with 3.5-, 4.2- and 9.2-Mb de novo microdeletions in Xq27.3-q28 containing FMR1. X-inactivation was random in all patients, yet they presented with ID/DD as well as speech delay, macrocephaly and other features attributable to FXS. No signs of autism were present. Here, we further delineate the clinical spectrum of female patients with microdeletions. FMR1 expression studies gave no evidence for an absolute threshold below which signs of FXS present. Since FMR1 expression is known to be highly variable between unrelated females, and since FMR1 mRNA levels have been suggested to be more similar among family members, we further explored the possibility of an intrafamilial effect. Interestingly, FMR1 mRNA levels in all 3 patients were significantly lower than in their respective mothers, which was shown to be specific for patients with microdeletions containing FMR1.

Epilepsy among children in Greenland.

INTRODUCTION: Epilepsy has been considered to be more frequent in Greenland than in Denmark, where the prevalence among children is 0.40%. STUDY DESIGN: Evaluation of the prevalence, diagnosis and treatment of epilepsy among children in Greenland aged 0-15 years. METHODS: During autumn 2000, 13 out of 18 hospitals in Greenland were visited. The population of children in the areas visited was 11,965 of a total of 15,226 in Greenland. All children with the diagnosis of epilepsy were referred for evaluation and the diagnosis was confirmed. When possible, informed consent was obtained to collect data from medical records. RESULTS: 43 children (18 boys) had the diagnosis of epilepsy. For 38 (15 boys) further data were obtained. Mean age was 8.5 years (3-14) for boys and 7.9 years (2-14) for girls. The age at diagnosis was 4.9 years (1-11) for boys and 4.2 years (0-10) for girls. The prevalence of epilepsy was 0.34%. In 31 cases an electroencephalograph (EEG) recording was done, comprising sleep recordings in 26 cases. Medication was according to recommendations in Denmark. CONCLUSION: The prevalence of epilepsy in children and the medical treatment of epilepsy among children in Greenland is the same as in Denmark.

Growth hormone treatment of patients with Prader-Willi syndrome. Swedish Growth Hormone Advisory Group.

Several studies have now been published on the effect of one or several years of growth hormone treatment on growth and body composition of children with Prader-Willi syndrome. The majority of the patients have responded with greatly increased growth rate, decreased body fat and increased muscle volume. Many of these children seem to have a functional growth hormone deficiency, probably secondary to their hypothalamic dysfunction. Further studies are needed to establish the long-term effect of this treatment on somatic and psychological well-being.

The sella turcica in children with lumbosacral myelomeningocele.

The purpose of the present study was to analyze the morphology of the sella turcica in children born with myelomeningocele. Profile radiographs from 16 children (nine females and seven males) born with myelomeningocele were analysed. The contour of the anterior wall of the sella turcica in myelomeningocele patients, instead of following the normal cranio-caudal direction, was always in an obliquely antero-posterior direction. The sella turcica thus appeared broad cranially with a diverging anterior wall, or with both diverging anterior and posterior walls. This appearance gave and impression of a wide sella turcica in myelomeningocele with less depth than normal. The investigation has drawn attention to the fact that congenital malformations in the axial skeleton, even though, as in the case of myelomeningocele, they are located far from the cranial base, may have manifested themselves in the cranial base as well. The pathogenetic relationship between these manifestations is to be found in the early embryonic structure, the notochord. With the concept of embryological developmental fields, defined as areas with a common developmental origin, such as the notochordal field involved in myelomeningocele, new ways seem to be emerging for an improvement of aetiologically based diagnosis and treatment.

Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably.

We have compared the growth and the body composition in children with Prader-Willi syndrome (PWS) with and without growth hormone treatment (recombinant GH 0.1 IU/kg/day) after a 1-y period. Twenty-nine prepubertal children with PWS, with mean body mass index (BMI) SDS of 2.2, and 10 (control) healthy obese children with mean BMI SDS of 5.6, underwent 24-h frequent blood sampling. Both PWS and control obese children had low and similar GH levels (0.7 microg/l +/- 0.4SD). Serum IGF-I levels, however, were significantly lower in children with PWS (-1.5SDS +/- 0.8SD vs -0.2SDS +/- 0.8SD). The 29 PWS children were randomized into 2 groups of 15 and 14 subjects for GH treatment and no treatment, respectively. Height velocity increased from -1.9SDS to + 6.0SDS in the treated group (p < 0.001) and decreased from -0.1SDS to -1.4SDS in the control PWS group during the study year. BMI decreased significantly for the treated group (+3.0SDS to +2.0SDS). Relative fat mass decreased significantly, while fat-free mass increased (p < 0.001) for the treated group. No significant changes were noticed in body composition in the control PWS group. In conclusion, the low spontaneous 24-h GH secretion, regardless of body weight, and the exceptional response to growth hormone treatment together with the finding of low IGF-I levels suggest that growth hormone deficiency is a common feature of PWS, as a result of hypothalamic dysfunction. Treatment with growth hormone is beneficial for the majority of PWS children.

Effects of growth hormone treatment on growth and body composition in Prader-Willi syndrome: a preliminary report. The Swedish National Growth Hormone Advisory Group.

A controlled, randomized study was conducted to assess the effect of growth hormone (GH) treatment on growth, body composition and behaviour in prepubertal children (3-12 years of age) with Prader-Willi syndrome. GH treatment was given to one group of 15 patients (group A) at a dose of 0.1 IU/kg/day for 2 years. The second group (group B; n = 12) was not treated for the first year and was then given GH at a dose of 0.2 IU/kg/day for the second year. All patients had low 24-hour levels of GH and insulin-like growth factor I before GH treatment. Height velocity SDS increased from -1.9 +/- 2.0 to 6.0 +/- 3.2 during the first year of GH treatment in group A, and from -1.4 +/- 1.2 to 10.1 +/- 3.9 in the second year of the study in group B. When GH treatment was stopped, height velocity declined dramatically. Height SDS followed a similar pattern. GH treatment reduced the percentage body fat and increased the muscle area of the thigh. Isometric muscle strength was also increased. In addition, GH treatment appeared to have psychological and behavioural benefits, which were reversed after cessation of treatment. It was concluded that GH treatment improves growth, body composition and behaviour in children with Prader-Willi syndrome.

Clinical features and molecular genetic analysis of a boy with Prader-Willi syndrome caused by an imprinting defect.

Prader-Willi syndrome (PWS) is a neuroendocrine disorder caused by a non-functioning paternally derived gene(s) within the chromosome region 15q11-q13. Most cases result from microscopically visible deletions of paternal origin, or maternal uniparental disomy of chromosome 15. In both instances no recurrence has been reported. In rare cases, PWS is associated with lack of gene expression from the paternal allele due to an imprinting defect. We report the clinical features and the molecular genetic analysis of the first Danish child with PWS due to a defect of the putative imprinting centre (IC). When the imprinting mutation is inherited from a carrier father, the risk that future children will be affected is theoretically 50%. It is therefore important that these families are referred to a geneticist for counselling and further investigation. Prenatal diagnosis is currently only feasible when the mutation has been identified in the affected child.

X-linked adrenal hypoplasia in a large Greenlandic family. Detection of a missense mutation (N4401) in the DAX-1 gene; implication for genetic counselling and carrier diagnosis.

X-linked congenital adrenal hypoplasia (AHC) is a developmental disorder of the human adrenal gland that results in profound hormonal deficiencies, which are lethal if untreated. Hypogonadotropic hypogonadism (HHG) is frequently associated with this disorder. The gene (DAX-1) responsible for the disease has recently been isolated. It encodes a protein with large similarity to members of the nuclear hormone receptor superfamily. Several different mutations in this gene have been found in patients suffering from AHC. We have identified a missense mutation (N440I) in three patients with AHC and HHG, all belonging to a large Greenlandic family. A total of 42 individuals has been tested for this mutation. We have diagnosed 10 women as carriers, and have excluded 22 women with a 25-50% risk from being carriers, emphasizing the rapid impact of molecular genetic techniques.

Biotinidase deficiency: two cases of very early presentation.

Two infants with early presentation of biotinidase deficiency (age 3 weeks and 2 weeks) are described. On admission, both children had severe neurological symptoms. In the first patient, magnetic resonance imaging (MRI) of the brain showed frontal and temporal atrophy, and in the second patient, CT of the brain showed diffuse periventricular hypodensities, particularly in the frontal region. Oral treatment with biotin (15mg and 10mg per day respectively) made all symptoms disappear within a few weeks. On follow-up 13 and 16 months later, both children were still asymptomatic on this treatment. Their psychomotor development was normal. MRI and CT of the brain had normalized. Later, a moderate hearing loss was detected in the first patient. In biotinidase deficiency, early diagnosis and treatment with oral biotin are essential in order to prevent irreversible damage to the central nervous system and early death from metabolic acidosis. Neonatal screening for biotinidase deficiency would fulfil this goal.

[Prader-Willi syndrome--clinical picture and genetics]. / Prader-Willi syndrom--kliniske billede og genetik.

Characteristics are hypotonia, problems with feeding and thriving in the neonate and infant, later hyperphagia and severe obesity. Other findings are dysmorphic traits, hypogonadism, short stature, developmental delay, mental retardation and behavioural problems. Diabetes mellitus (NIDDM) is frequent in adults. Treatment is symptomatic. Prognosis is determined by obesity. PWS occurs almost always sporadically and is found in all ethnic groups and in both sexes. The epidemiology of PWS in Denmark is unknown. In 95% of cases with PWS cytogenetic and molecular genetic investigations show either deletion of the paternal chromosome 15q11q13 or uniparental maternal disomy of chromosome 15. Since 1992 150 bloodsamples of patients suspected for PWS have been investigated by cytogenetic and molecular genetic techniques at the John F. Kennedy Institute, DK-2600 Glostrup; deletion of the paternal chromosome 15 was found in 15 and uniparental maternal disomy of chromosome 15 in eight cases.

[Utilization of medical services for children in an area of Copenhagen]. / Børns forbrug af laege i et københavnsk lokalområde.

As part of the development of models for community services for children, the utilization of the medical services for children in a local area in Copenhagen viz the catchment region of the Osterbro Social Centre was reviewed. By means of contact investigations in the above mentioned region with the general practitioners and duty roster doctors in two selected weeks and by information from the Casualty Department Register in the University Hospital and from the National Danish Patient Register, the pattern of illness for children aged 0-14 years and utilization of medical services in the year 1986 was described. Utilization of casualty departments was uniform throughout childhood. In the course of one year, every third child, on an average, had had contact with a casualty department. This is in contrast with other sections of medical services where utilization decreases with increasing age of the child. The frequency of admission to hospital was high, particularly for the youngest children. The majority of all contacts were on account of infectious diseases. A community, multidisciplinary effort to reduce ill health is suggested to combat the many illnesses due to infection, the numerous contacts with doctors and hospital admission. Choice of doctor in cases of acute illness in children is discussed.

[CT in children with epilepsy. The value of cerebral CT in children with epilepsy]. / CT hos børn med epilepsi. Vaerdien af cerebral CT hos børn med epilepsi.

In a retrospective material of 66 children with epilepsy, computed tomographic scanning had been undertaken in 30 cases. Abnormal computed tomographic findings were observed in five children in the form of cerebral tumour or sequelae of head injuries or perinatal asphyxia. All five children had focal EEG changes but none of these as the only positive finding. The investigation had therapeutic consequences in one case only, viz the case where computed tomographic scanning confirmed the clinical suspicion of tumour. The value of computed tomographic scanning in children with epilepsy is discussed, particularly in children with focal EEG changes.