Ring 14

rarechromo.org

Sources
The informationin this leaflet
comes from the
medical literatureand from
Unique’smembers with
Ring 14(referenced U),
who weresurveyed in 2004.
At the time of
publication,
Unique had 28
members withring 14.
Unique is very
grateful to thefamilies who took
part in the survey.

References
The informationin this leaflet isdrawn partly fromthe publishedmedical literature.
The first-named
author andpublication dateare given to allow
you to look forthe abstracts ororiginal articles on
the internet in
PubMed. If you
wish, you canobtain abstracts
and articles from
Unique.

Ring 14
Ring 14 syndrome is a rare genetic disorder. Typically,children with ring 14 have a delay in development, some levelof learning difficulty, seizures and may have a high rate ofrespiratory infections.
Ring 14 is caused by a rearrangement of one of thechromosomes in the cells of the body. Chromosomes are themicroscopically small structures within the nucleus of thecells that carry information in the form of genes that enables
healthy, normal development. Chromosomes come in pairs ofdifferent sizes and apart from the sex chromosomes (two Xs
for a girl and an X and a Y for a boy), they are numberedfrom largest to smallest approximately according to size fromnumber 1 to number 22.
Chromosomes have a top (short) arm called p and a bottom(long) arm called q. In people with ring 14, both ends of one
chromosome 14 have broken off and joined to form a circle,
usually leaving out some chromosome material and genes.
The p arm of chromosome 14 is very small and can usually belost without apparent harm because similar genes areavailable on other chromosomes, so many of the effects ofring 14 are believed to be caused by losing genes from the qarm.
The long arm typically breaks at bands 14q32.2 or 32.3,
although breaks at 14q31 and 14q24 are also known.
Whatever the amount of chromosome material lost, the mainfeatures seem to be usually the same (Schmidt 1981; Fryns 1982;
Wintle 1995).

Mosaicism
Most people with ring 14 have the ring chromosome in all
their body cells. Some people have some cells with the ring
chromosome and some with a different chromosome makeup. This is called mosaicism and your geneticist will tell you if
this is what your child has.
Mosaicism appears to result in similar features to full ring 14
syndrome. Three people have been described in the medical
literature, including a mother of average intellectual ability
who suffered seizures during early childhood and was
discovered to have ring 14 after the birth of a more severely
affected daughter, also with ring 14. A Unique member who ismosaic for ring 14 is particularly severely affected (Gilgenkrantz
1984; Rethore 1984; Portoian-Shuhaiber 1986; Matalon 1990; U).

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short(p)arm

Formation of ring
chromosome 14. Breakpoints- vary from person toperson. The breakpoints
shown are typical.

14

Families
say …
She is extremely
loving andaffectionate. She
also likes to tease
us and play games.
She has anadorable laugh andis quite bright andintelligent. She isalso physically
beautiful,somewhat exotic
looking.
Eli has terrificpresence!

long
(q)
arm

Main features• Learning disability. The level is variable and depends tosome extent on the frequency and severity of seizures.
The ability to learn can be within the normal range• Developmental delay• Seizures. These are of variable types and are typically hard
to control. Occasionally children outgrow seizures• Repeated infections, especially respiratory(Zelante 1991; Morimoto 2003; Casas 2005).

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How rare
is ring 14?
It is not known
how manypeople havering 14 but they
are certainly
rare. More than
40 people havebeen describedin the medical
literature butthese only
represent afraction of thetotal. When
this leaflet was
published,
Unique had 28
members witha ring 14
chromosome(Ono 1999).

Other features• Hypotonia (floppiness, low muscle tone), usually apparent
soon after birth• Slow growth during pregnancy, small to normal size at birthand sometimes slow postnatal growth• Microcephaly (an unusually small head)• White, yellow or grey spots on the retina and/ or greyish

colouring specifically of the macular area, a part of the retina.
This does not affect vision. The retina, at the back of the eye, isthe place where light signals entering the eye are converted into
nerve signals to the brain

•
•
•
•

Feeding difficulties and problems with weight gain
Distinct facial features
Puffy hands and/ or feet. The feet may be flat
Pale or coffee-coloured patches of skin
(Lippe 1981; Schmidt 1981; Fryns 1982; Zelante 1991)

LifespanBabies born with ring 14 typically have no major organ defects
and neonatal respiratory difficulties are not usually severe. So
most people with ring 14 are quite healthy.
However, seizures are an almost universal feature and can beserious. Parents can expect to be trained to manage a longlasting seizure or one that occurs at night. Some parents havebought infrared video cameras to allow observation during sleep(Lippe 1981; Riley 1981; U).

Growth and appearance
A child with ring 14 will look much like other children, although
she or he may well be short. In one series, 24/33 children were
unusually short and in the Unique survey 7/11 children wereshort for their age. Mean birthweight is low at 2578g/ 5lb 11oz
and intrauterine growth retardation may be the first prenatal
marker of the syndrome. Postnatal growth patterns are variable
and may be normal. Some children in the Unique survey grew atan uneven pace with periods of no growth interspersed with
rapid catch-up (Riley 1981; de Blois 1990; Matalon 1990; Zelante 1991; U).
A disproportionately small head is typical and was noted in 28/32
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children. In the Unique series at least 7/11 children had microcephaly. Five children
whose overall size was recorded as small also had a proportionately small head
(Zelante 1991; U).

The facial features that experienced doctors notice may not be obvious to parents.
Although none of the parents surveyed by Unique mentioned their child’s
appearance as being out of the ordinary, the following features have been noted as
typical by doctors: epicanthic folds (skin folds across the inner corner of the eye)
26/26: high forehead 21/21; long, narrow palpebral fissures (openings for the eyes);oval face 20/22; broad nasal bridge 19/27; short neck (with extra skin, sometimes
described as ‘buffalo hump’) 18/27; flat occiput (back of the head) 9/15;
dolicocephaly (a long, narrow head shape) 9/16; micrognathia (a small lower jaw)
9/20; low set ears 10/24. A high palate is also common and was noted in 14/19
children. However, some children with ring 14 do not fit this facial stereotype (deBlois 1990; Zelante 1991; Morimoto 2003).
Eli and his chromosomes

Ring 14Below
Age 4, with the dolphins

5Seizures
All children with ring 14 syndrome known to Unique and reported in the medical
literature have developed seizures. Combined data from the medical literature andthe Unique survey show that most babies (18/29) had their first seizure at 6-9months. Only six babies were affected at three months or less and in another fivethe first seizure occurred between 12 and 28 months. There is one child whosestory is on a ring 14 website (see Sources of Support) who had not developed
seizures at the age of 8 years (Zelante 1991; Morimoto 2003; U).
Seizures are of varying types and most children have more than one type. The typemay vary in one child with age. Seizures may occur cyclically or be associated withsleep and with waking. Among the triggers noticed by parents are childhood
infections, fevers and accidents. In around half of children MRI and CT scans haverevealed underlying brain pathology. Although electroencephalogram (EEG)
anomalies were found in 16/20 children, there was no single typical pattern (Sparkes
1977; de Blois 1990; Zelante 1991; Shirasaka 1992; Ono 1999; Morimoto 2003; U).
Despite the reputedly intractable nature of seizures in children with ring 14, theUnique survey shows that in many seizures are controlled or their frequency ismarkedly reduced by a dynamic policy of multi-drug therapy using newer
antiepileptic medications. A small number of children become seizure-free and many
have weeks or months of remission. In most other children medication markedly
reduces the frequency of seizures, although they remain hard to control. One
Unique member had a seizure-free spell of two years, another adult in Unique has
been seizure-free without medication since the age of 3 and there is a research
report of an adult with ring 14 who outgrew seizures at the age of 2½ (Riley 1981;
Morimoto 2003; U).

Learning and education
Children with ring 14 syndrome typically face some degree of learning disability andchildren usually thrive best in a school equipped to teach children with moderate toprofound learning difficulties. However, some people have no learning disability.
Research reports and the Unique survey agree that thelevel of disability is variable. Out of fifteen Unique
She does little things
members whose intellectual ability was scored, nine werethat amaze us. She
rated severe, five moderate and one was too young forseems to know moreassessment.
than most give her
Somechildren learn to read and write. Lisa, at 20, could
credit for.
write her name and one or two numbers, read lettersand one or two words and could count to 20. Moretypically, Unique members do not learn to write. Many
families and medical researchers report that seizures affect a child’s learning ability
although the effect may be transient (Lippe 1981; Riley 1981; Schmidt 1981; Howard 1988;
Matalon 1990; Zelante 1991; Morimoto 2003).

6Speech and communication
Half of Unique’s members use at least some words.
Typically, first words emerged in the third or fourth year
Chris is good atand one girl speaks fluently. Lisa, who started to talk atremembering somenine months, could communicate needs, feelings andthings but cannot
opinions and used complex sentences. Unless she wascommunicate back.
agitated from a seizure ‘her communication skills are
excellent!’ her mother reported. Chris, at 8, asked simple
questions like ‘Where’s my mum?’ or made appropriate
remarks like ‘Yum! Yum!’
Other members used single words and supplemented speech with signing, gestures,
eye pointing, picture exchange systems and vocal noises. In a pair of three-year-old
twins, each with ring 14, one had a vocabulary of five to 10 words while the other
had no speech but followed two to three-word instructions.
Some children show understanding in advance of expressive language. In his thirdyear, Matteo was using a few words but understanding complex three-partcommands and at 10 Joanne was able to follow instructions.
Most families noted that speech and language was more limited when seizures were
frequent and five families specifically recorded deterioration over time in speech
and language (Sparkes 1977; U).

Sitting, moving, walking
The evidence from the Unique survey is of a variable delay
Matteo’sin motor development. In a few children the delay was
psychomotor
minor but most started to sit and walk very late. One ordevelopment is not
two did not walk. Acquiring advanced mobility skills was
homogeneous. In
also variable, with some children cycling, climbing andsome areas he’s
dancing while others depended on walking aids andabsolutely in line
support. The hypotonia that many people with ring 14
with his age and insyndrome experience is a major factor and all children
others, like language
benefit from physiotherapy and occupational therapy.
and concentration,
These snapshot observations provide an insight into
he is delayed.
the range of mobility experience of Unique members.
• Chloe, at 2, walked, ran, climbed up and down stairs and was learning to kick aball• Eli started walking with support at 30 months. At 3, he could take a few steps but
preferred to crawl or use a walker, in which he also liked to dance. He enjoyedswimming, swinging and bouncing• Cameron walked for two months from 14 months. After a setback with seizures
he learned to walk again at 20 months• Anneliese walked at three and at eight walked well on her own but preferred awheelchair for long distances• Kenneth, at 13, could not walk or sit• Lisa, at 20, loved to walk long distances for exercise
7Medical concerns
Typically, children have no major organ defects. There are three reports inthe medical literature of children with heart murmurs. The Unique survey
revealed no members with heart defects (Amarose 1980; Lippe 1981; U).

Respiratory infections
Vulnerability to infection, particularly respiratory infections, is fairly
common, reported in 8/37 children in one series and 10/15 Uniquemembers of all ages. In one child frequent respiratory infections were areason for cytogenetic referral, in another they were reported as the only
health problem. It is known that some children with ring 14 are
immunodeficient and it has recently been shown that two children with low
immunoglobulin (antibody) levels in their blood were missing one or moreof a cluster of genes (known as IGH) in band 14q32.33 that are importantfor making immunoglobulins. All children with ring 14 who have lost any of
the IGH genes and any children who catch repeated infections arerecommended to have a blood test to check their immunoglobulin levels. Iflevels are low and the child has repeated infections, treatment withintravenous immunoglobulin should be considered.
The research group that recently identified the loss of IGH genes as apossible cause of repeated infection also suspects that giving intravenous
immunoglobulin may help with seizure control. In this context, the family of
a 12-year-old reported to Unique that better seizure control and fewer
respiratory infections went hand in hand (Schmidt 1981; de Blois 1990; Zelante 1991;
Casas 2005; U).

Retinal anomalies
White, yellow or grey spots on the retina and/ or greyish colouring of themacular area of the eye have been reported in 12/22 people. These spots
do not affect vision and families are usually unaware of them. One Uniquefamily reported abnormal retinal pigmentation (Schmidt 1981; Zelante 1991; U).

Genital anomalies
Undescended testes with or without hypospadias, where the hole usually atthe end of the penis is on the underside instead, have been reported twice
in medical literature and noted in one Unique member (Dzarlieva 1977; Lippe
1981; Matalon 1990; Kristensen 1992; U).

Lymphoedema of the hands and feet (puffy hands and feet)
This has been described in the medical literature but not by Uniquemembers. The feet may also be flat (Iselius 1980; Zelante 1991).
Other conditions have been described singly or in only one or two children
and may not be typical of ring 14. They include intention tremor(movements directed at a goal produce shaking or trembling in the moving
body parts, especially the hands); early childhood stroke (at 6 months);8

glaucoma; ectopic right kidney and supernumerary kidney; cartilaginous growths; asmall pituitary gland with a cyst; hearing impairment; torticollis, also known as a wry
neck, a condition in which the head tilts towards one shoulder and the chin rotates
towards the opposite shoulder; hydrocephalus (an abnormal increase in the amountof cerebrospinal fluid inside the ventricles of the brain); and dislocated knees (Iselius
1980; Riley 1981; Schmidt 1981; Fryns 1982; Portoian 1986; Wintle 1995; U).

Other concerns
Teeth
Unusual patterns of teething have been reported by two Unique families and in one
research report. One child had late emergence of teeth, with none visible at age
one; another had early teething; a third was born with two teeth. On removal, two‘jelly-like’ teeth appeared in their place (Lippe 1981; U).

Skin
Unusual skin pigmentation is often described and may be a marker of mosaicism.
Patterns include linear pigmentation, irregular vitiligo, linear café au lait spots on theabdomen and buttocks and dark & white streaks & whorls, as well as light spots on
the trunk and coffee-coloured spots on the abdomen. Only two Unique members
had abnormal pigmentation and in one child it was minimal (Schmidt 1981; de Blois 1990;
Zelante 1991; U).

Behaviour
There has been no formal survey of the effects of ring 14 on
behaviour. This information comes from the Unique survey.
Most families did not report behaviour problems. A minority offamilies reported overactivity and hyperactivity. It is notknown whether hyperactivity is a side effect of medication, ageneral characteristic or a part of ring 14 syndrome. These
snapshot descriptions come from Unique families:• At 2, unable to play other than fleetingly• At 2, too hyperactive to complete psychological testing.
Especially hyperactive during a seizure-prone phase. Spellsof maturation are noted to alternate with regression during
seizure crises• At 3, hyperactivity had improved since vagal nerve
stimulation in which a battery-powered device similar to apacemaker was implanted under the skin delivering mildelectrical stimulation to the brain via the vagus nerve.
Therapy can reduce the severity and frequency of seizures insome patients• At 20, had outgrown the hyperactivity and attention
disorder she experienced as a youngster and preferred tospend her time quietly alone

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When she started
lamotrigine (forseizures), shebegan to display
aggressive
behaviour(kicking, biting,pulling hair) when
she didn’t get her
own way. We
now give her
choices and warn
her of an
approachingchange in herschedule. We
also use a lowdose tranquilliser.
She is muchbetter now.

If he feels
threatened, he will
resist any attempts
to co-operate.

• A small number of families reported challenging
behaviour:• At 4, could be restless, pull hair and throw objects• At 8, resisted everything you ask him to do• At 12, showed frustration by hitting and biting

Independence
Most children with ring 14 syndrome who have beenstudied have experienced considerable developmental
delay. They have difficulty in communicating their needs
and in co-ordinating the actions of daily living. For thisreason, they are likely to need support throughout theirlives.
The level of self care people reach is quite individual.
Unique’s members include people who are able to dress
and feed themselves and are fully continent as well as
adults who need round the clock care.

Food and eating
Ring 14 syndrome does not appear to cause any specificfeeding problems. However, people with chromosome
disorders often have difficulties with feeding. For babies,
these include difficulty coordinating swallowing withsucking, gastro oesophageal reflux, where feeds andstomach contents return into the gullet and are often
vomited or may be inhaled, and poor weight gain.
Children may continue to accept a limited range of
textures and quantities or on the other hand may
overload their mouth and fail to chew. Antiepileptic
medications may cause nausea and so suppress appetite
but more commonly cause an increase in appetite,
reported by some Unique families as voracious (Lippe 1981;
Riley 1981; Matalon 1990; U)

Will the pregnancy be different?
Pregnancy is usually unremarkable, but by the second
trimester slow growth may be apparent and may well be
the only sign on the mid-pregnancy anomaly scan. Ring
14 can be detected during pregnancy by examining cells
obtained by chorion villus sampling at around 11 weeks
or by amniocentesis around 15 to16 weeks.

10Did this happen due to something I did wrong?
Rearrangements occur in chromosomes as part of evolution. They affect children
from all parts of the world and from all types of background. They also happen
naturally in plants and animals. So there is no reason to suggest that your lifestyle oranything that you did caused the ring chromosome to form.

Why did this happen?
Has the child inherited the ring 14 from a parent?
About 99 per cent of ring chromosomes occur out of the blue. Geneticists call thistype of event de novo, which means that the child with the chromosome disorder isthe only person in the family with the chromosome disorder. A blood test will thenreveal that both parents have chromosomes without rearrangements that could
have caused ring 14 and their chances of having another affected baby are usually nogreater than for anyone else.
What are the chances of a parent with ring 14 passing the ring on to theirchildren?
Very occasionally ring 14 may be passed from mother to child. Father-to-childtransmission has not been recorded, perhaps because the ring chromosome insome way interferes with sperm creation. This suggests that boys with ring 14 may
not be fertile as adults (Riley 1981; Matalon 1990).

A karyotype of a boy with ring 14. This would be written 46,XY,r(14)11Support and Information

Rare Chromosome Disorder Support Group,
G1, The Stables, Station Road West, Oxted, Surrey RH8 9EE, United Kingdom
Tel/Fax: +44(0)1883 723356
info@rarechromo.org I www.rarechromo.org

Join Unique for family links, information and support.
Unique is a charity without government funding, existing entirely on donations
and grants. If you can, please make a donation via our website atwww.rarechromo.org Please help us to help you!
Ring 14 is a support group for families affected by ring 14 syndrome. The centre
is in Italy but it operates worldwide and aims to disseminate information and topromote and fund research.
www.ring14.org
Via Flavio Gioia 542124 Reggio Emilia
ITALY Tel : +39 0522 421037 Fax +39 348 9500941 info@ring14.org
There is a Facebook group for Ring 14 at www.facebook.com/groups/ring14
Unique lists external message boards and websites in order to be helpful to families
looking for information and support. This does not imply that we endorse their content or
have any responsibility for it.
This information guide is not a substitute for personal medical advice. Families should
consult a medically qualified clinician in all matters relating to genetic diagnosis,
management and health. Information on genetic changes is a very fast-moving field andwhile the information in this guide is believed to be the best available at the time of
publication, some facts may later change. Unique does its best to keep abreast ofchanging information and to review its published guides as needed. The guide wascompiled by Unique and reviewed by Dr Melanie Manning, clinical instructor, Divisions of
Cytogenetics and Medical Genetics, Stanford University School of Medicine, California andby Professor Maj Hultén BSc PhD MD FRCPath, Professor of Reproductive Genetics,
University of Warwick, UK 2004. (PM)Copyright© Unique 2005

Rare Chromosome Disorder Support Group Charity Number 1110661
Registered in England and Wales Company Number 5460413

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