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New Treatments for Mental retardation and Chromosomal Abnormalities

Fragile X syndrome. This is the most common form of mental retardation in males and it occurs in 1:1500 males. These children, besides having mental retardation, have sort of unusual behavior. They may have autistic-type features, they tend to get frustrated and have this sort of hand-flapping behavior. They have large ears and a long face. After puberty these boys may develop macroorchidism. The diagnosis is a molecular diagnosis.

Prader-Willi syndrome. Just so you know, the American Academy of Pediatrics has established care guidelines and management guidelines for individuals with Prader-Willi. These individuals have an incidence of 1:10,000 to 1:25,000. Even though we see this classic large child who is obese with small genitals in the older childhood years and adult years.

The diagnosis of Prader-Willi now is by molecular study, a methylation study, and it rules out uniparental disomy and the imprinting mutation, and FISH for chromosome 15. So we do both studies together now. If you just did the FISH alone you would be missing about a quarter of the patients with Prader-Willi.

Management is behavioral modification to prevent obesity. There are trials going on right now to treat these children with growth hormone and there is talk about starting very early in life.

A related syndrome to Prader-Willi is Angelman’s syndrome, and this is a slide from the Journal of Child Neurology in 1992, and these are kids who have prominent jaws. The have this kind of happy appearance. These kids are ataxic so they tend to hold their hands up in the air. The old name for this disorder was Happy Puppet syndrome.

Another form of mental retardation that we see in our patients, Down syndrome. This child is another model for the Lands End catalog. He is saying hi and showing you his small hands. He has fifth digit clinodactyly. You can make believe you can see his transverse palmar crease. He has short palpebral fissures that are slightly up-slanting, small ears, flat mid-face. So individuals with Down syndrome have mental retardation, frequently short stature, short skull, brachycephaly, up-slanted palpebral fissures, small ears, flat mid-face, protruding tongue.

Diagnosis is by chromosome study, even though in many cases it’s a clear cut clinical diagnosis. Ninety-five percent of individuals with Down syndrome will have trisomy 21 from an non-disjunction event, 5% have translocation, and those 5% that do have translocations, you need to do the parents chromosomes because they have a risk of having more children.

There are AAP guidelines for management of individuals with Down syndrome, but two of the issues that come up quite frequently in the care of individuals with Down syndrome.

Another form of developmental delay that we see, and that I think is the most difficult to diagnose, is fetal alcohol syndrome. You really need a good history of maternal alcohol use and you really need to rule out other genetic causes. There have been a number of kids with fetal alcohol syndrome who finally got some chromosomes done and it was a chromosomal abnormality. So you need to be sure that a differential diagnosis is generated.

Another mental retardation disorder that we see is Smith-Lemli-Opitz syndrome and this is a very severe form of mental retardation, where these children have severe failure to thrive, microcephaly, ptosis, cataracts, small jaw, cleft palate and abnormal genitals. This slide shows children with Smith-Lemli-Opitz. They have these flat, droopy facies.

The treatment is a diet that’s very high in cholesterol. There are a lot of studies going on through Boston Children’s Hospital and there’s a study in Oregon that we’ve participated in.

Approach to a child with congenital heart disease; additional history you need to get in a child with congenital heart disease. Is the type of congenital heart disease that’s present electrolyte disturbances, particularly calcium? Kids with Williams syndrome tend to have hypercalcemia. Kids with 22Q deletion syndrome, or DiGeorge syndrome, will have hypocalcemia.

So again, features in 22Q deletion syndrome, hypocalcemia, thymic hypoplasia, cleft palate and developmental delay. The reason I keep bringing this up is that it is becoming more and more common. Some of the newer numbers I’ve seen are estimating the incidence as about 1:2,000.

Supravalvular aortic stenosis is the common lesion that we see in individuals with Williams syndrome. The can also have peripheral pulmonic stenosis. So Williams syndrome; these kids have developmental delay, hypercalcemia, dysmorphic features with stellate irises, thick lips, puffy eyes, cocktail party personality. Again, the diagnosis is by FISH.

Down syndrome; the common congenital heart disease that we see in Down syndrome is an AV canal. Here’s the model from the Lands End catalog. He’s got small ears, he’s got clinodactyly and you can kind of see his transverse crease.

Individuals with Turner’s syndrome can have congenital heart disease, and you need to look for that in girls with Turner’s syndrome. Here is a young woman. She has neck webbing, wide spaced nipples, a wide carrying angle.

Critically ill newborn with abnormal features and a potentially lethal syndrome. Trisomy 18. The incidence is about 1:8,000 live births. Frequently caused by trisomy of all of chromosome 18. Although occasionally you can have some translocations.

Trisomy 13. These kids have low birth weight, but actually the average birth weight - if you are into collecting trivia - is about 2600 gm, so it’s not terrible. These kids are microcephalic, holoprosencephaly can be found in trisomy 13. These kids can have scalp ulcerations and you sometimes think, "Is that a scalp electrode mark?"

So an infant with an abnormal skeletal configuration. A neonatal disorder that we see is osteogenesis imperfecta, and type II is the lethal variety. The radiographic findings are crumpled long bones and wormian bones of the skull. This is resulting from under ossification.

Another neonatal lethal disorder is thanatophoric dysplasia. This is the most common neonatal lethal skeletal dysplasia. Some of the forms have a cloverleaf skull and it is short-limbed dwarfism. These children can have severe brain malformations if they did survive.

The approach to a child with skeletal abnormality; dwarfism, achondroplasia and the AP has guidelines for care of children with achondroplasia. Short stature, short limbs - it’s called rhizomelica. One of the clues is that if you have a person lift up their arm, their elbow is below their ear. Vertebral body abnormalities, trident hand. If you have the person hold out their hand they can’t bring all their fingers together. These kids have small foramen magnums.

Management; these kids are at increased risk for SIDS so that needs to be discussed with parents of a child with achondroplasia. These kids have a small foramen magnum so they are at risk for hydrocephalus and C-spine injuries, and a small thorax.

Kids with tall stature. We talked a bit about Marfan’s syndrome before. This is a gentleman showing you his arachnodactyly.