Vanja A. Holm

A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map.

Although familial recurrences of Rett syndrome (RTT) comprise only approximately 1% of the reported cases, it is these cases that hold the key for the understanding of the genetic basis of the disorder. Families in which RTT occurs in mother and daughter, aunt and niece, and half sisters are consistent with dominant inheritance and variable expressivity of the phenotype. Recurrence of RTT in sisters is likely due to germ-line mosaicism in one of the parents, rather than to recessive inheritance. The exclusive occurrence of classic RTT in females led to the hypothesis that it is X-linked and may be lethal in males. In an X-linked dominant disorder, unaffected obligate-carrier females would be expected to show nonrandom or skewed inactivation of the X chromosome bearing the mutant allele. We investigated the X chromosome inactivation (XCI) patterns in the female members of a newly identified family with recurrence of RTT in a maternal aunt and a niece. Skewing of XCI is present in the obligate carrier in this family, supporting the hypothesis that RTT is an X-linked disorder. However, evaluation of the XCI pattern in the mother of affected half sisters shows random XCI, suggesting germ-line mosaicism as the cause of repeated transmission in this family. To determine which regions of the X chromosome were inherited concordantly/discordantly by the probands, we genotyped the individuals in the aunt-niece family and two previously reported pairs of half sisters. These combined exclusion-mapping data allow us to exclude the RTT locus from the interval between DXS1053 in Xp22.2 and DXS1222 in Xq22.3. This represents an extension of the previous exclusion map.

Growth Hormone Secretion in Prader‐Willi Syndrome

ABSTRACT. Integrated 12‐hour growth hormone secretion studies, peak growth hormone response to clonidine provocation. Somatomedin‐C levels, T‐4 and TSH levels were studied in six growth‐retarded children with the Prader‐Willi syndrome, of whom five had a 15 q‐karyotype. Only one of the subjects was obese. All showed abnormally low growth hormone secretion. None achieved a nocturnal peak above 10 μg/l, none had a mean nocturnal level over 1.8, and none showed a level above 8 μg/l after clonidine provocation. These findings contrasted with normal TSH in all and normal T‐4 in five. These findings suggest that the poor linear growth in the Prader‐Willi syndrome is caused by a true deficiency of growth hormone secretion, and that the low growth hormone levels observed in such cases are not an artifact of obesity

Prader-Willi Syndrome and Scoliosis

Of 37 patients with the Prader‐Willi syndrome for whom spinal x‐rays were available, 32 had a structural scoliosis of 10o or greater. Kyphosis was also found to be more common in older persons with this syndrome, occurring in only one of 14 adolescents but in five of 10 adults. The scoliosis was analyzed in infantile, juvenile, adolescent and adult subgroups. The results suggest that the scoliosis is present from an early age and remains stable during childhood, but progresses in 15 to 20 per cent of cases during adolescence. Scoliosis in patients with Prader‐Willi syndrome has many of the clinical characteristics encountered in idiopathic scoliosis. Because it is difficult to détéct in these individuals, the authors recommended that baseline spinal x‐rays be obtained in all such patients who have suspicious asymmetry of the spine, followed by regular clinical examination, especially during adolescence.

Rett's syndrome: a progressive developmental disability in girls.

Two girls are described who had normal physical and mental development during the first few months of life, documented on home movies in one. Gross motor development slowed during the second half of the first year followed by loss of acquired vocabulary and deterioration of fine motor skills. Linear growth and head growth decelerated. Stereotyped hand movements appeared around 2 to 3 years of age. Early appropriate social responses faded into a vacant stare. Neurological development was characterized by early hypotonia followed by ataxia and finally spasticity. One girls has been followed through adolescence. Additional symptoms in later childhood and adolescence included scoliosis, episodes of hyperpnea, vasomotor disturbances of the legs, and precocious puberty. The patients fit the criteria for a progressive neurological disorder called Retts syndrome, which results in profound developmental disability and occurs only in girls. Etiology remains unknown

Scoliosis in the Rett syndrome

Of 32 patients with classical Rett syndrome, radiographs of the spine could be obtained in 30; two had moved. Five (17%), ranging in age from 3.2-11.5 years, had a curve of 10 degrees or less. Twenty-five (83%) had scoliosis. The age at first diagnosis of scoliosis ranged from 4.3 to 18 years of age. The curves ranged from 10 degrees to 86 degrees at a mean age of 14.9 years. Eight of the 21 curves, 38 percent, showed progression, which was first noticed from just before 5 to after 18 years of age. Bracing was done in five of the younger girls with progressive curves at ages 8.3-10.4 years. Three required surgery, performed at ages 10.9, 16.2 and 17.3 years respectively. Physicians following these patients need to refer them for orthopedic care at the first suspicious sign of scoliosis. Orthopedic surgeons taking care of children with the Rett syndrome (RS) should be aware of the clinical unpredictability of the scoliosis in this condition.

Cognitive and psychiatric variability in three brothers with fragile X syndrome

Three brothers were determined to have the fragile X syndrome. While sharing physical characteristics, their developmental and behavioral characteristics were diverse, as was the severity of the disorder. Each brother had evidence of developmental problems but demonstrated heterogeneity of presentation in the same sibship.

Rett Syndrome: A Case Report from an Audiovisual Program

A case report of a 13-yr-6-mo-old girl with the Rett syndrome is provided from an audiovisual program featuring home movies taken from 2 mos of age and onward. The patient shows the following symptoms not previously emphasized in the Rett syndrome: deceleration of head growth (rather than acquired microcephaly), fall-off in linear growth in infancy, early hypotonia, precocious puberty and respiratory alkalosis. Except for the precocious puberty, a second, 35-mo-old, patient has followed the same clinical course with similar laboratory findings.

A Two-Year Follow-Up of Autistic Children Treated with Fenfluramine

Six children with autism, who were treated with fenfluramine as part of a multi-center double-blind placebo-controlled crossover design study, were continued on an open trial of this medication. Follow-up evaluation of these children after 27 months indicated that numerous problems arose in the management of these children, most often resulting in discontinuation of the medication. Particularly noted were development of tolerance, appetite and weight problems, and requirements for other kinds of interventions including introduction of other psychotropic medications and change in custodial circumstances.

Tenth annual scientific conference of the Prader-Willi Syndrome Association (USA), July 19, 1995, Seattle, Washington

Each year for the last 10 years, scientists conducting research on Prader-Willi syndrome have come together to exchange information during a scientific conference held in conjunction with the annual Prader-Willi Syndrome Association (USA) meeting. Presentations based on submitted abstracts encompass such varied fields as genetics, endocrinology, pediatrics, nutrition, psychology, psychiatry, and education. This year`s scientific conference was held in Seattle, Washington, on July 19, 1995, in conjunction with the 14th PWSA (USA) meeting held July 20-23. Seventeen reports were presented at the scientific meeting, the abstracts of which follow.