Kousseff syndrome: a causally heterogeneous disorder.

The existence of Kousseff syndrome as a distinct entity has been thrown into doubt by a recent study conducted on the family originally reported by Kousseff. In all cases where chromosome 22q11.2 FISH testing has been undertaken, including the original sibship, a chromosome 22q11.2-microdeletion has been identified. We report two cases of sacral myelomeningocele associated with a conotruncal cardiac anomaly or "Kousseff syndrome." The first case, a 4-year-old girl, had a sacral myelomeningocele, tetralogy of Fallot, microcephaly, hydrocephalus, hypoplasia of the corpus callosum and mild-moderate developmental delay. Chromosome 22q11.2 FISH was normal and the facial phenotype was not that of velocardiofacial syndrome. Sequencing of the entire coding region of CITED2 did not reveal a mutation. The second case, a male infant, was found to have a 22q11.2-microdeletion. These cases confirm Kousseff syndrome to be a causally heterogeneous disorder.

Mowat-Wilson syndrome.

MWS is a multiple congenital anomaly syndrome, first clinically delineated by Mowat et al in 1998. Over 45 cases have now been reported. All patients have typical dysmorphic features in association with severe intellectual disability, and nearly all have microcephaly and seizures. Congenital anomalies, including Hirschsprung disease (HSCR), congenital heart disease, hypospadias, genitourinary anomalies, agenesis of the corpus callosum, and short stature are common. The syndrome is the result of heterozygous deletions or truncating mutations of the ZFHX1B (SIP1) gene on chromosome 2q22.

Epilepsy and associated psychopathology in young people with intellectual disability.

OBJECTIVE: This study aimed to investigate the role of epilepsy in psychopathology among an epidemiological sample of young people with intellectual disability (ID). The study also compared behavioural and emotional problems in young people on medication to control their epilepsy with those not on medication, and young people with epilepsy who were having current seizure activity with those with no current seizure activity. METHODOLOGY: An epidemiological cohort of 392 participants, representative of the general Australian population of young people with ID, were used in the study. One hundred and fifteen individuals from this cohort were identified as suffering from epilepsy. The Developmental Behaviour Checklist was used to measure symptoms of behavioural and emotional disturbance. RESULTS: Results confirmed that young people with ID and epilepsy did not differ from controls without epilepsy on measures of psychopathology. Furthermore, those with epilepsy on medication had no difference in levels of problem behaviours than epileptics not on medication. CONCLUSIONS: The results suggest that epilepsy has little or no influence on problem behaviours for young people with ID. Our attempt to understand the pathogenesis of behaviour problems in persons with ID may be better directed towards understanding genetic mechanisms than epilepsy pathologies.

Maternal phenylketonuria: a continuing problem.

OBJECTIVES: To estimate the number of women of childbearing age in New South Wales whose children are at risk of the maternal phenylketonuria (PKU) syndrome (intellectual disability, microcephaly, congenital malformations). SETTING: New South Wales, 1996. DESIGN: Comparison of number of women with PKU aged 15-44 years on the NSW PKU database (observed number) with expected number derived from population data. MAIN OUTCOME MEASURES: Observed and expected numbers of women with PKU (defined as blood phenylalanine levels > or = 400 mumol/L, and phenylalanine-restricted diet recommended) by age; number with no clinical contact with the PKU service in previous year; outcomes of pregnancies in women with PKU (January 1994 to July 1996). RESULTS: 110 women aged 15-44 years with PKU were listed on the database. The expected number was 145 (95% confidence interval, 122-171). The difference was greatest in the 30-44 years age group (born before comprehensive newborn screening), with only 55% of the expected number listed. Sixteen women who had been diagnosed with PKU at birth were not having regular follow-up, while 18 women had been diagnosed only after investigation of abnormalities in their children. Of 28 pregnancies managed by the NSW PKU service, 19 were considered unaffected by the maternal PKU syndrome and five affected (another three did not reach term; one outcome was unknown). Of 46 unmanaged pregnancies, all were affected. CONCLUSION: There is an urgent need for better follow-up of women with PKU and for education of health professionals about the MPKU syndrome, its recognition, the risks of untreated pregnancy and the benefits of dietary treatment.

Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23.

We have identified six children with a distinctive facial phenotype in association with mental retardation (MR), microcephaly, and short stature, four of whom presented with Hirschsprung (HSCR) disease in the neonatal period. HSCR was diagnosed in a further child at the age of 3 years after investigation for severe chronic constipation and another child, identified as sharing the same facial phenotype, had chronic constipation, but did not have HSCR. One of our patients has an interstitial deletion of chromosome 2, del(2)(q21q23). These children strongly resemble the patient reported by Lurie et al with HSCR and dysmorphic features associated with del(2)(q22q23). All patients have been isolated cases, suggesting a contiguous gene syndrome or a dominant single gene disorder involving a locus for HSCR located at 2q22-q23. Review of published reports suggests that there is significant phenotypic and genetic heterogeneity within the group of patients with HSCR, MR, and microcephaly. In particular, our patients appear to have a separate disorder from Goldberg-Shprintzen syndrome, for which autosomal recessive inheritance has been proposed because of sib recurrence and consanguinity in some families.