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New Treatments for Chromosomal Abnormalities

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 thatís present electrolyte disturbances, particularly calcium? Kids with Williams syndrome tend to have hypercalcemia. Kids with 22Q deletion syndrome, or DiGeorge syndrome, will have hypocalcemia. If facial dysmorphism is present in these children and if there is developmental and behavior problems on top of congenital heart disease. So cono-truncal heart defects are commonly found in 22Q deletion syndrome, DiGeorge and velocardiofacial syndrome. So when you have a child with a cono-truncal heart.

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 Iíve seen are estimating the incidence as about 1:2,000. These children classically, when they push them over to the DiGeorge side of the phenotype, they kind of classically have a round face and a broad nose. The kids with the velocardiofacial phenotype.

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.

Down syndrome; the common congenital heart disease that we see in Down syndrome is an AV canal. Hereís the model from the Lands End catalog. Heís got small ears, heís got clinodactyly.

Individuals with Turnerís syndrome can have congenital heart disease, and you need to look for that in girls with Turnerís syndrome. Here is a young woman. She has neck webbing, wide spaced nipples, a wide carrying angle. And individuals with Turnerís syndrome can have coarctation of aorta.

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. About 10% of the individuals are mosaic, and that means that they may have a normal cell line as well as their trisomic cell line. So one of the things that we see in trisomy 18 is prenatal growth deficiency. These kids tend to be microcephalic. Their occiputs tend to be fairly prominent, small mouth and jaw. In fact, thatís a really important clue because one of the things that youíll get in the history when people bring that baby back from the delivery room is that they had a terrible time trying to intubate this baby.

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 itís 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?" It may not be if there are other things going on. Iris coloboma is common.

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. These babies have a narrow chest, theyíll have a blue sclera and usually more than the usual baby sclera. Most babies have bluish sclera but these kids have really blue sclera. The death in these children is usually due to the inability to ventilate and also intracranial hemorrhages. There are mutations in collagen 1A1 and 1A2 genes. This is a radiograph of a baby that I saw about two years ago and these are his crumpled long bones, and hereís the skull x-ray. Basically you donít see mineralization of the calvariae. There are just little bits of mineralization. When you feel the childís skull it kind of feels like a

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, and they have mutations in a gene called fibroblast growth factor receptor 3. This is a child showing a very narrow chest and generally the way that these children die is they just canít be ventilated because their chest cavity is so small that you canít expand their lungs.

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 - itís 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 canít bring all their fingers together. These kids have small foramen magnums. Some can have C-spine compression so you need to look for long track signs in these kids. Again, this is caused by a mutation in fibroblast growth factor receptor 3. Itís autosomal dominant and itís the most common cause of dwarfism. Hereís a young lady with achondroplasia. She has a prominent forehead, she has a big head for her size, saddle nose. Sheís got sort of a narrow chest and had a lot of problems with pneumoniaís early on. Trident hand. She has sort of redundant skin. Itís kind of like her skin wanted to grow but her bones didnít. So kids get this kind of "Michelin tire" effect.

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 Marfanís syndrome before. This is a gentleman showing you his arachnodactyly. This is a dislocated lens and these persons have tall stature, hyper-mobility, scoliosis, dislocated lenses, aortic dilatation is a big issue and this is the way these individuals pass away, so you need to look at that.

Management issues in these individuals; they need follow-up by cardiology with annual echoís, they need ophthalmic follow-up. There is a syndrome called homocystinuria thatís metabolic that can be ruled out by plasma amino acids, that we use as part of the diagnostic criteria. Cardiologists frequently put their patients on beta-blockers to slow down the dilatation of the aorta.

Another group of disorders are skeletal abnormalities of craniosynostosis and these are disorders characterized by premature closure of the cranial sutures. Most of these patients have mutations in one of the fibroblast growth factor receptor genes. Other genes that have also been implicated in craniosynostosis are TWIST and MSX1. And this is just showing the cranial sutures. Most of the syndromes involve premature closure of the coronal sutures. This is an

So this is the last section. When to look for malignancy in a child with congenital malformations. Beckwith-Wiedemann syndrome. This is a disorder where children are large for gestational age, tend to have organomegaly, a large tongue, can present with a large omphalocele and they have a 7.5% incidence of tumors, predominantly Wilms tumor, adrenal cortical carcinoma and hepatoblastoma. If you have a 36-weeker who weighs over 4 kg this is something to think

Sotos syndrome is another overgrowth disorder with excessive growth and a large head, narrow facies, hypertelorism, a large jaw and diabetes. These individuals can develop the same tumors. So the rule of thumb with these kids with overgrowth disorders is to get q.3 to q.6 months abdominal ultrasounds looking for these tumors. This is a young lady with Sotos syndrome. These children tend to have a long face with an upturned nose and frontal bossing. This is a