Miscellaneous genetic disorders: Pathology review

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Case Study0:00–0:37

At the clinic, 30 year old Linda comes with her 2 year old toddler for a yearly pediatric checkup. Linda tells the pediatrician that, while she was bathing her son, she noticed that his testes are unusually large.
Clinical examination confirms enlarged testes, and additionally, the pediatrician noticed dysmorphic facial features including a long, narrow face; prominent forehead and jaw; and large, protruding ears.
Later that day, 27 year old Samantha comes to the clinic with her 5 year old son because she noticed that he often has strange episodes of laughter and smiling.
In addition, she mentions that he had experienced seizures several months ago. Based on the clinical findings, the pediatrician concludes that both children have some form of genetic disorder, and orders genetic testing to confirm the diagnosis.

Pathology0:37–0:54

Now, let’s go over genetic disorders such as fragile X syndrome, imprinting disorders, Cri-du-chat syndrome, and Williams syndrome.First, let’s start with fragile X syndrome.

Fragile X syndrome0:54–2:12

This is an X-linked disorder caused by inactivation of the FMR1 gene, which is located on the long arm of the X chromosome.
These individuals have over 200 CGG trinucleotide repeats on the FMR1 gene, which leads to its hypermethylation and subsequent inactivation.
Fragile X syndrome is the most common cause of inherited intellectual disability, and the second most common cause of genetically associated psychiatric disorders, after Down syndrome.
Individuals with fragile X syndrome can have delayed speech and motor development. In addition, individuals may have anxiety disorders, autism, and attention deficit-hyperactivity disorder; as well as mitral valve prolapse.
For your exam, it’s important to know the key physical findings of fragile X syndrome includes enlarged testes, also known as macroorchidism; and dysmorphic facial features, like a long narrow face, with large protruding ears, and prominent forehead and jaw.
The treatment of fragile X syndrome includes speech, occupational, and physical therapy. Clinicians should also focus on the prevention of common medical problems associated with the disorder such as gastroesophageal reflux, sinusitis, and otitis media.Now, let’s move on to imprinting disorders.

Imprinting disorders2:12–3:44

For most genes, both the maternal and paternal copies are expressed. However, certain genes undergo a normal process called genomic imprinting, where they are silenced via methylation depending on which parent passes them down.
Some genes are supposed to be silenced if they are passed down the paternal side, and some are silenced only if they come from the maternal side.
Now, imprinting disorders can be caused by defects in the imprinting process, or due to uniparental disomy, which occurs when a person receives two copies of the same chromosome.
Now if both chromosomes come from the father, the child won’t have any active paternally imprinted genes associated with that chromosome.
Imprinting disorders may occur sporadically, or can be passed down from an asymptomatic parent. Let’s say in this case, a maternal imprinted gene is mutated and does not work.
A biological male gets the mutated gene from their mother, but they’ll be asymptomatic since the maternal version is silenced.
However if they pass on this mutated gene to their children, they’ll have a paternal version of the gene that’s active and can develop the disease.
Two well known imprinting disorders are Prader-Willi syndrome and Angelman syndrome. It’s important to note that both syndromes involve defects in chromosome 15, but in Prader-Willi syndrome, the maternal gene is imprinted, so the defect usually comes from the paternal gene.
On the other hand, in AngelMan syndrome, the paternal gene is normally imprinted so the defect is in the maternal gene.Now, let’s focus on Prader-Willi syndrome.
In 75 percent of cases, there’s a deletion or mutation of paternal genes from chromosome 15. In the other 25 percent of cases, this syndrome can occur due to maternal uniparental disomy.

Prader-Willi syndrome3:44–4:48

Now, common clinical findings of Prader-Willi syndrome include hyperphagia, obesity, short stature, intellectual disability, and hypotonia, which commonly appears as a floppy baby syndrome.
In addition, individuals with Prader-Willi syndrome may develop hypothalamic dysfunction, which can lead to hypogonadism, hypothyroidism, adrenal insufficiency, and growth hormone deficiency.
The diagnosis of Prader-Willi syndrome can be confirmed using chromosomal or microarray analysis; and work-up should also include evaluation for thyroid and adrenal function, as well as growth hormone secretion.
There’s no cure for Prader-Willi syndrome, but they may get mental health care, controlled diet and exercise programs, as well as growth hormone therapy.
Moving on to Angelman syndrome, in 95 percent of cases, there’s a mutation or deletion of the maternal UBE3A gene on chromosome 15.

Angelman syndrome4:48–5:33

The remaining 5 percent of cases are caused by paternal uniparental disomy, The clinical presentation of Angelman syndrome includes seizures, ataxia, severe intellectual disability.
They tend to have a happy demeanor and often laugh inappropriately. The diagnosis of Angelman syndrome can be confirmed through genetic studies showing loss of function of the UBE3A gene.
Again, there’s no cure for Angelman syndrome, but individuals may get physiotherapy, speech therapy, and symptomatic treatment like anticonvulsant medications to control seizures.All right, let’s switch gears to Cri-du-chat syndrome, also known as 5p deletion syndrome or 5p minus syndrome.

Cri-du-chat syndrome5:33–6:15

This is a rare autosomal disorder caused by a congenital microdeletion of the short arm of chromosome 5. For your exam, it’s important to know that the most characteristic finding is high-pitched crying and meowing done by infants, and in fact Cri du chat means the cry of the cat.
Other common clinical findings include microcephaly, moderate to severe intellectual disability, epicanthal folds, cardiac abnormalities, such as ventricular septal defect, and hypertelorism, which is an increased distance between the eyes.Next, we have Williams syndrome, which is an autosomal dominant disorder caused by a congenital microdeletion of the long arm of chromosome 7.

Williams syndrome6:15–7:16

For your exams, remember that the deleted region often includes the elastin gene which can lead to vascular abnormalities like supravalvular aortic stenosis and renal artery stenosis.
One of the biggest clues for this disorder is that these individuals often have the characteristic “cocktail party” personality, which includes excellent verbal skills, extreme friendliness with strangers, and a lack of social inhibition.
Other common clinical findings include mild to moderate intellectual disability and distinctive "elfin" facies, which is described as a flat nasal bridge, short upturned nose, long medial cleft, periorbital puffiness, full lips, wide mouth, broad forehead, medial eyebrow flare.
In addition, individuals with Williams syndrome can have increased sensitivity to vitamin D and subsequent hypercalcemia, which can be managed with a diet restricting vitamin D and calcium.
All right, as a quick recap. Fragile X syndrome is an X-linked disorder caused by the inactivation of the FMR1 gene.

Review7:16–8:47

Fragile X syndrome presents with intellectual disability and psychiatric disorders, as well as enlarged testes, dysmorphic facial features, delayed speech and motor development, and mitral valve prolapse.
Next, Prader-Willi syndrome can be caused by a mutation in the paternal gene of chromosome 15; or by maternal uniparental disomy.
Common clinical findings include hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia. On the other hand, Angelman syndrome can be caused by a mutation of the maternal UBE3A gene of chromosome 15; or by paternal uniparental disomy.
Key findings include seizures, ataxia, severe intellectual disability, and inappropriate laughter. Next, Cri-du-chat syndrome is an autosomal disorder caused by a congenital microdeletion of the short arm of chromosome 5.
Common clinical findings include microcephaly, moderate to severe intellectual disability, epicanthal folds, cardiac abnormalities, and hypertelorism.
Finally, Williams syndrome is an autosomal dominant disorder involving a congenital microdeletion of the long arm of chromosome 7.
Key findings include excellent verbal skills, lack of social inhibition, intellectual disability, "elfin" facies, cardiovascular abnormalities, and hypercalcemia.Now back to our cases.

Summary8:47–9:22

The key to the diagnoses of these disorders is to recognize their characteristic clinical findings and order genetic testing.
Linda’s toddler has enlarged testes and dysmorphic facial features, including a long, narrow face; prominent forehead and jaw; and large, protruding ears.
These are classical findings for fragile X syndrome. On the other hand, Samantha’s son has unprovoked episodes of laughter and smiling.
This in combination with neurological problems like seizures should make you suspect Angelman syndrome. In both cases, genetic testing confirmed the suspected diagnosis.
Miscellaneous genetic disorders: Video and Causes | Osmosis