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Miscellaneous genetic disorders: Pathology review


Content Reviewers:

Antonella Melani, MD

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.

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.

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.

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.

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.