Tuesday, July 11, 2017

5q14.3 deletions

Inspired by a patient

Is there a 5q14.3 deletion syndrome?

At the moment, very few people have been reported with a molecular diagnosis of a
5q14.3 deletion. However, the reports that exist show remarkable similarities. These
similarities are listed below and constitute an emerging syndrome.

Most likely features
 Early and severe hypotonia [low muscle tone]
 Marked developmental delay
 Marked learning disability and need for special support
 Marked delay in learning to sit and move
 Marked language delay. Most children do not speak but communicate in other ways
 Delay in making eye contact
 Stereotypic or unusual movements
 Some unusual facial features
 Brain abnormalities on magnetic resonance imaging [MRI]…


Most babies and children with a 5q14.3 deletion have seizures but in many the seizures
improve and in some they stop altogether. Out of 20 children with a 5q14.3 deletion
that includes the entire MEF2C gene, all bar one 18-month-old child have had seizures
and he was found to have an abnormal EEG [electroencephalogram recording of the
wave patterns from the continuous tiny electrical signals coming from the brain].
In most children, seizures start in the first year, often before six months; in one baby
they started on the first day of life and in another at 16 months. One child has only had
febrile seizures [see page 6], has not been diagnosed with epilepsy and at the age of 4 is
not taking anti-epileptic drugs [AEDs]. Another 13-month-old girl with a history of an
abnormal EEG and seizure-like episodes which appear as an involuntary upward eye
gaze is being investigated for the possibility that these are not in fact seizures.

Among three children with a partial deletion of the MEF2C gene, two have seizures,
while a three-year-old boy has no seizures and a normal EEG. Among nine children
with a 5q14.3 deletion, the oldest 15, but where the MEF2C gene is preserved intact,
five have not had seizures. Among the four who have seizures, they started later in one
child – at 4 years 9 months – than is typical in children who have lost the MEF2C gene…

Absent or severely delayed speech

While a typically-developing baby usually coos and babbles by six months, produces
speech-like noises in the next months and says understandable words around their first
birthday, speech and language development in a baby with a 5q14.3 deletion is different.
Overall, progress is slower but one Unique baby was cooing at eight months; another
knew to ask or say baba when she was hungry at 14 months; others are making a range
of vowel and consonant sounds or babbling [mama, baba, dada] by seven months to
three years. One child is saying single words [no, bottle, mama, Elmo, yeah] by 20
months but others only use words years later, if at all.

Children with a 5q14.3 deletion draw on a rich variety of alternatives to speech and
language. They may use subtle facial expressions, smile, cry, laugh or look sad, they may
use modified signs, body language, pushing things away or pulling them close. They may
shout or make vocal noises. They may mimic sounds but not in a meaningful context.
As they mature, some children use alternative communication aids such as picture
exchange systems or electronic speaking aids.

Once reasonably consistent eye contact has been established, babies can let you know
when they have understood you – and by and large they understand better than they
can speak. A baby who can hold his gaze can watch your mouth as you talk. All the
same, children need time to process even one-word instructions like ‘No’ and their low
muscle tone means that they have difficulty complying. One 22-month-old baby can,
with time, show that he understands he should lift his legs up [nappy change]; arms up
[dressing]; or open his mouth for medicine - but he cannot yet carry out the actions.
Children qualify for speech and language therapy but typically start in their second or
third year and all families find it helpful.


Park SM, Kim JM, Kim GW, Kim HS, Kim BS, Kim MB, Ko HC. 5q14.3 Microdeletions: 
A Contiguous Gene Syndrome with Capillary Malformation-Arteriovenous Malformation 
Syndrome and Neurologic Findings. Pediatr Dermatol. 2017 Mar;34(2):156-159. 


Deletions within chromosome region 5q14.3q15 have been
associated with a spectrum of disorders including developmental delay,
hypotonia, absent speech, mild facial dysmorphism, seizures, and brain
anomalies. Some cases of concomitant neurologic abnormalities and cutaneous
vascular malformation associated with 5q14.3 deletion have been reported.
Previously reported cases had similar features, including multiple capillary
malformations, and neurologic abnormalities, including epilepsy, hypotonia, and
developmental delay. We report a case of 5q14.3 neurocutaneous syndrome
presenting with multiple capillary malformations, neurologic abnormalities, and
microdeletion in chromosome 5q14.3.

Ilari R, Agosta G, Bacino C. 5q14.3 deletion neurocutaneous syndrome: Contiguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C: A progressive disease. Am J Med Genet A. 2016 Mar;170(3):688-93.

We report the case of a young girl who was presented with complex clinical symptoms caused by the deletion of contiguous genes: RASA1 and MEF2C, located on chromosome 5q14.3. Specifically, the diagnosis of her skin disorder and vascular malformations involving central nervous system is consistent with a RASopathy. The child's neurological manifestations are observed in most patients suffering from 5q14.3 by deletion or mutation of the MEF2C gene. A review of the literature allowed us to conclude that the contiguous deletion of genes RASA1 and MEF2C fulfills the criteria for the diagnosis of a Neurocutaneous syndrome as proposed by Carr et al. [2011]. We also assessed the penetrance of RASA1 and clinical manifestations of MEF2C according to the type of deletion. This child described presents the complete symptomatology of both deleted genes. We would also like to highlight the progression of the disorder.

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