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1p36 deletion syndrome

This is part of Rare diseases.

Diagnosis: 1p36 deletion syndrome

Synonyms: Partial monosomy 1p36 syndrome

Innehåll


Date of publication: 2013-12-27
Version: 3.0

The disease

1p36 deletion syndrome is characterized by delayed growth, malformations, moderate to severe intellectual disability, seizures, hearing and vision impairment, and certain particular facial features. The syndrome is also known as partial monosomy 1p36 syndrome and deletion 1p36-syndrome.

The condition is caused by a small deletion (loss of a segment of DNA) on the short arm (p) of chromosome 1. The deletions causing the disorder are often so small that they are called microdeletions and they cannot be detected by traditional chromosome analysis.

The first people with 1p36 deletion syndrome were identified in the 1980s. However, since many of these individuals also had other chromosomal abnormalities, their symptoms varied widely. Improved techniques for chromosome analysis have been developed since the late 1990’s, making it possible to identify more cases, and to increase understanding of the disorder.

Occurrence

1p36 deletion syndrome is one of the most common microdeletion syndromes. It is estimated that between 10 and 20 children out of every 100,000 are born with the syndrome, meaning that in Sweden between 10 and 20 children are born with the condition annually. There are probably between 200 and 300 children and young people under the age of 18 with the syndrome living in Sweden. The syndrome is twice as common in girls than boys.

However, the incidence may be higher as a normal chromosome analysis often does not reveal the abnormality, so a number of cases may go undiagnosed. It is estimated that about one per cent of people with cognitive impairments of unknown cause may have a 1p36 deletion.

Cause

The syndrome is caused by a chromosomal abnormality, where there is a missing segment, a deletion, on the short arm (p) of chromosome 1. This means that there is only one copy of the genes included in the deletion, rather than the normal two. It is this genetic imbalance that causes the symptoms.

Different types of changes in chromosomal region 1p36 have been described. The nature of the symptoms depends on the type of chromosomal abnormality. Most individuals with the syndrome have a genetic aberration which affects 1p only. Usually this is a terminal deletion, where the outermost part of the chromosome is missing, and about 50 per cent of people with 1p36 deletion syndrome have this type of deletion. In slightly less than a third of people the outermost part of the chromosome is intact, but there is a deletion nearer the middle of the chromosome (an interstitial deletion).

Sometimes 1p36 deletion syndrome arises because the child inherits a chromosomal abnormality known as an unbalanced chromosome translocation from a parent with a balanced translocation. As well as having a deleted region on chromosome 1, the child also has excess genetic material (a duplication) from another chromosome. The extra copies of genes from the other chromosome often cause further symptoms, in addition to those associated with 1p36 deletion syndrome.

There are also other complex chromosomal abnormalities in the 1p36 region which may cause the syndrome.

Several genes important to the development of the foetus and child are located in the 1p36 region and symptoms presenting in individuals with the syndrome are a result of the loss of one copy of the genes in this location. The loss of several adjacent genes on a chromosome is known as “contiguous gene syndrome”. There is no clear correlation between the size of the chromosome deletion and the severity of the symptoms.

There are indications that there is a critical region of the chromosome which, if deleted, causes most of the symptoms of the syndrome.

Sometimes the deletion comprises a larger region than 1p36, and in these cases additional symptoms present.

Heredity

In the majority of cases (about 80 per cent), the deletion only affects the 1p36 region. Most of these deletions are new mutations that occur during the formation of sex cells (gametes), and the risk of the parents having more children with the syndrome is very small. The deletion is slightly more likely to occur in the chromosome copy inherited from the mother than the one inherited from the father.

Approximately 10 per cent of children with the syndrome have inherited a translocation chromosome from one parent. A translocation occurs when a segment from one chromosome changes place with a segment from another chromosome. If the exchange does not cause any loss or excess of chromosomal material, the translocation is said to be balanced. If a parent has a balanced translocation the risk of having another child with 1p36 deletion syndrome is higher than if the disorder was the result of a new mutation. The estimated risk of recurrence is between 10 and 15 per cent, but may vary.

Usually, balanced translocations do not cause symptoms in the carrier, but in the formation of gametes (eggs and sperm) unbalanced translocations of chromosomes may occur. Female carriers of the balanced translocation may find it difficult to become pregnant; they might miscarry, or give birth to a child with an unbalanced chromosomal abnormality. Unbalanced translocations usually cause intellectual disabilities, impaired growth, and/or congenital malformations. The child, as well as having a genetic deletion in chromosome 1, also has three copies of another chromosomal region, and they often affect the nature of the symptoms.

Symptoms

Malformations

About half of the children with the syndrome have some form of heart defect. The severity of the defects varies considerably, as many different heart abnormalities may occur. One example is patent ductus arteriosus, when the blood vessel connecting the pulmonary artery and the aorta fails to close after birth. Two other heart problems are an abnormal hole in the wall between the chambers of the heart (ventricular septum defect), or a combination of heart defects (the tetralogy of Fallot). Another example is dilated cardiomyopathy, in which the heart becomes abnormally enlarged.

Approximately one-third of children with the syndrome have some clefting of the lip, jaw, or palate. The severity of the deformity varies. Small children with cleft palate may have difficulties eating, and speech problems often arise. The teeth and the bite might also be affected. All children with 1p36 deletion syndrome who have a cleft palate lack a copy of a gene called SKI. However, as most of the children with both the syndrome and the SKI deletion do not have cleft palates, other factors are thought to be involved.

Around 20 per cent of the children have malformations of the kidneys or the urinary tract, which include kidneys not being located in their usual position, renal pelvis dilation and cysts. These malformations do not normally interfere with kidney function, although they increase the risk of urinary tract infections that can cause kidney problems.

Some individuals with the syndrome have anomalies of the central nervous system, such as hydrocephalus or cerebral atrophy, which are visible on X-ray or magnetic resonance pictures.

Skeletal malformations, such as scoliosis, rib anomalies, and lower-limb asymmetry are relatively common. Unusual symptoms include telangiectatic skin lesions (affecting the blood vessels in the skin) and brown patches on the skin. Malformations of the gastro-intestinal tract can also occur.

Growth

Most newborn infants with the syndrome have a congenital growth abnormality. Some children are of normal size at birth but then grow more slowly than their peers. In many children, head circumference is abnormally small (microcephaly). The degree of growth impairment varies between individuals. Some children grow very quickly, have an excessive appetite, and are overweight.

Thyroid function may be affected. Around one fifth of children with the syndrome have low thyroid function (hypothyroidism), leading to slow metabolism and fatigue. Both early and delayed puberty have been reported, and boys with the syndrome may have underdeveloped genitals.

Epilepsy

The majority of children with the condition have epilepsy. The type of epilepsy varies and most types of seizure may occur. Often seizures begin during the child’s first year of life. About one fifth of infants have a form of epilepsy known as infantile spasms characterized by series of sudden contractions of the arms, or the arms being flung out. The KCNAB2 gene, located on chromosome region 1p36, is associated with epilepsy. If the deletion includes this gene, the child frequently has a severe form of epilepsy.

Development

All individuals with 1p36 deletion syndrome have some degree of intellectual and language-related disability. The degree of the intellectual disability varies but is usually moderate to severe. However, there are some children with only a mild cognitive impairment. Individuals with intellectual disability require more time to understand things, and learn new skills. They have difficulties learning, processing information and dealing with new situations. It may also be hard to take a holistic view of situations, and to understand and interpret associations. Under these circumstances it may take longer to express wishes, thoughts, and feelings. Above all the syndrome affects the ability to speak (expressive language disorder) as well as being associated with difficulties in understanding.

Speech tends to be more severely affected than motor function, although motor development is usually severely delayed. Children learn to sit, stand and walk later than their peers. They often have low muscle tone (muscular hypotonia), which can lead to sucking and feeding problems. Hypermobility of the joints is common, which can affect motor development.

Behavioural disturbances have been reported in almost half of the children. These include temper tantrums, self-destructive behaviour, and repetitive behaviour (stereotypies) such as rocking or hand waving. Some children have an abnormally large appetite which, if not controlled, can lead to obesity.

Both speech and motor development tend to improve as the child grows older. Behavioural problems also often decrease with age.

Vision

Vision problems such as strabismus (squinting), refraction errors, and cataracts are common.

Hearing

About 50 per cent of children have impaired hearing. Hearing loss may primarily affect the ability to hear high frequencies, or affect all sound frequencies. Hearing loss is often the result of the nervous system failing to transmit signals normally (sensorineural hearing loss). However, in some children, sound vibrations cannot be conducted effectively to the inner ear (conductive hearing loss), for example after ear infections.

Other points

Many children with 1p36 deletion syndrome have certain characteristic features. These include a small head (microcephaly), a flat area at the back of the skull (brachycephaly), a prominent forehead, straight eyebrows, deeply set eyes with an epithelial fold, flat nose and nasal bridge, short midface, low set ears, small mouth with down-turned corners, pointed chin, and asymmetric face.

The large anterior fontanelle closes later than normal in infants with the syndrome. Fontanelle closure, when the bony plates of the skull fuse, is regulated by the MMP23 gene in the 1p36 region. It is likely that the loss of one copy of this gene causes the late fusion of the fontanelle.

Diagnosis

The diagnosis is made on the basis of clinical symptoms and is then confirmed by chromosome or DNA analyses. Traditional chromosome analysis is normally performed by culturing white blood cells (lymphocytes) from a blood sample. However, this method effectively detects large deletions, but may fail to identify the microdeletions associated with 1p36, which require other methods of genetic analysis. Smaller chromosomal abnormalities can be identified by sensitive diagnostic tools such as FISH, MPLA and array CGH.

At the time of diagnosis it is important that the family is offered genetic counselling. If the underlying cause of the 1p36 deletion is an unbalanced translocation, both parents should be offered screening for chromosomal abnormalities. If either is found to be carrying a chromosomal abnormality, his or her close relatives should also be offered genetic screening, as they may also be carriers.

Prenatal diagnosis is an option.

Treatment/interventions

There is currently no cure for the disorder and efforts are directed at relieving symptoms. Much can be done to support the individual and compensate as much as possible for functional limitations.

As most people with 1p36 deletion syndrome experience symptoms from several organs it may be necessary to see several different specialists. Such visits will involve the examination and monitoring of the affected organs.

During the neonatal period the infant should have a cardiac ultrasound examination (echocardiogram). A paediatric cardiologist will plan interventions as appropriate. Some heart complications require surgery.

When the child is diagnosed, an ultrasound scan of the kidneys should also be carried out as abnormalities are associated with an increased risk of urinary infections and impaired renal function.

EEG (an electroencephalogram) and MRI (magnetic resonance image) scans of the brain should be considered. The EEG can reveal abnormalities associated with epilepsy and the MRI shows anatomical anomalies in the structure of the brain. Epilepsy is treated medically, although in 20 per cent of children, the seizures are difficult to treat. However, many children do not have seizures.

As even minor clefting can make it more difficult for the child to eat, a thorough examination of the palate and palatal function should be carried out at an early stage. Clefting requires surgical repair. This procedure is performed by a plastic surgeon and is carried out in several steps. Early contact with a paediatric dentist may be required. In order to ensure that children with sucking and eating difficulties receive sufficient nourishment parents may need help from a nutrition team, which includes professionals such as dieticians and speech therapists. When feeding is difficult, a feeding tube directly into the stomach, a PEG (percutaneous endoscopic gastrostomy), may be necessary for a period of time.

As vision problems are common, the child should be examined by an ophthalmologist. Some children will need eyeglasses. Cataracts are treated surgically and strabismus is treated by training of the affected eye by wearing a patch on the unaffected eye.

Hearing impairment may be progressive, and audiological evaluations should be performed regularly. The child’s ability to hear high frequencies should be assessed.

Thyroid function should also be examined regularly. An under-active thyroid should be treated.

Habilitation

Habilitation, including hearing and vision habilitation, should be started at an early age in order to stimulate the child’s development and help compensate for physical limitations. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. Help is available within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It may also include information about support offered by Swedish public agencies as well as advice on the way accommodation and other environments can be adapted to the child’s needs. Parents and siblings can also receive support. The family may also need help in coordinating different forms of help.

Habilitation measures focus on existing needs, may vary over time and occur in collaboration with individuals close to the child. Many children require contact with a speech therapist for assessment and to stimulate the development of language and communication skills as well as oral motor skills. Augmentative and alternative communication (AAC), a collective name for non-verbal forms of communication, should be made available from an early age. This can include the use of signs or pictures, depending on the child’s level of intellectual development.

Swedish public agencies can offer different forms of support to facilitate the family’s everyday life. Respite care can, for example, take the form of a contact family or short-term accommodation outside the home.

If parents wish, they should also be offered the opportunity to contact other families in a similar situation with whom they can share their experiences. Social and psychological support is important.

Adults with the syndrome usually require continued habilitative interventions and daily life support, for example in the form of special housing, offering assistance in managing daily living skills and organizing activities.

Practical advice

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National and regional resources in Sweden

In Sweden, the diagnosis is confirmed at one of the six Swedish university hospital departments of clinical genetics.

Resource personnel

Senior Physician Britt-Marie Anderlid, The Astrid Lindgren Children’s Hospital/Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00, email: britt-marie.anderlid@karolinska.se.

Professor Göran Annerén, Department of Clinical Genetics, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 59 42, fax: +46 18 55 40 25, email: goran.anneren@akademiska.se.

Courses, exchanges of experience, recreation

At Uppsala University Children’s Hospital a centre for children with chromosome disorders and other syndromes (“Syndromcentrum”) arranges day-long courses on selected subjects for children and their parents. Information is available from Senior Physician Ulrika Wester Oxelgren, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 68 39, www.akademiska.se/syndromcentrum.

A multidisciplinary team with experience of chromosome disorders and other syndromes is based at Karolinska University Hospital, Solna. These medical professionals are also involved in consultations and examinations. Contact: Eva Ekblom (Coordinator), Centre for Rare Diagnoses, Clinical Genetics, Karolinska University Hospital, Solna, Stockholm, Sweden. Tel: +46 8 517 75 626, email: sallsyntadiagnoser@karolinska.se.

Organizations for the disabled/patient associations

FUB, The Swedish National Association for Persons with Intellectual Disabilities, Gävlegatan 18B, Stockholm. Sweden. Mailing address: Box 6436, SE-113 82 Stockholm, Sweden. Tel:+46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

NOC, The Swedish National Network for Rare Chromosome Disorders is an affiliate of FUB. Among other things, the network arranges family meetings for the exchange of information and experience. Email: info@noc.fub.se, www.noc.fub.se.

Courses, exchanges of experience for personnel

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Research and development (R&D)

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Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under “Mer hos oss” in the column on the right-hand side.

The Ågrenska National Competence Centre for Rare Diseases has published a newsletter on 1p36 syndrome, nr 447 (2013). Newsletters are edited summaries of lectures delivered at family and adult visits to Ågrenska. They can be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 3191 19 79, email: agrenska@agrenska.se. Material for printing is available on www.agrenska.se.

Literature

Bahi-Buisson N, Guttierrez-Delicado E, Soufflet C, Rio M, Daire VC, Lacombe D et al. Spectrum of epilepsy in terminal 1p36 deletion syndrome. Epilepsia 2008; 49: 509-515.

Battaglia A, Hoyme HE, Dallapiccola B, Zackai E, Hudgins L, McDonald-McGinn D et al. Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation. Pediatrics 2008; 121: 404-410.

Gajecka M, Mackay KL, Shaffer LG. Monosomy 1p36 deletion syndrome. Am J Med Genet C Semin Med Genet 2007; 145C: 346-356.

Gajecka M, Yu W, Ballif BC, Glotzbach CD, Bailey KA, Shaw CA et al. Delineation of mechanisms and regions of dosage imbalance in complex rearrangements of 1p36 leads to a putative gene for regulation of cranial suture closure. Eur J Hum Genet 2005; 13: 139-149.

Heilstedt HA, Ballif BC, Howard LA, Kashork CD, Schaffer LG. Population data suggest that deletions of 1p36 are a relatively common chromosome abnormality. Clin Genet 2003; 13: 310-316.

Heilstedt HA, Ballif BC, Howard LA, Lewis RA, Stal S, Kashork CD. Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome. Am J Hum Genet 2003; 72: 1200-1212.

Heilstedt HA, Burgess DL, Anderson AE, Chedrawi A, Tharp B, Lee O et al. Loss of the potassium channel beta-subunit gene, KCNAB2, is associated with epilepsy in patients with 1p36.3 deletion syndrome. Epilepsia 2001; 42: 1103-1111.

Kang SH, Scheffer A, Ou Z, Li J, Scaglia F, Belmont J et al. Identification of proximal 1p36 deletions using array-CGH: a possible new syndrome. Clin Genet 2007; 72: 329-338.

Redon R, Rio M, Gregory SG, Cooper RA, Fiegler H, Sanlaville D et al. Tiling path resolution mapping of constitutional 1p36 deletions by array-CGH: contiguous gene deletion or “deletion with positional effect” syndrome? J Med Genet 2005; 42: 166-171.

Shaffer LG, Heilstedt HA. Terminal deletion of 1p36. Lancet 2001; 358 Suppl: S9.

Shapira SK, McCaskill C, Northrup H, Spikes AS, Elder FF, Sutton VR et al. Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome. Am J Hum Genet 1997; 61: 642-650.

Slavotinek A, Shaffer LG, Shapira SK. Monosomy 1p36. J Med Genet 1999; 36: 657-663.

Wu YQ, Heilstedt HA, Bedell JA, May KM, Starkey DE, McPherson JD et al. Molecular refinement of the 1p36 deletion syndrome reveals size diversity and a preponderance of maternally derived deletions. Hum Mol Genet 1999; 8: 313-321.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: monosomy 1p36 syndrome

GeneReviews (University of Washington)
www.genetests.org (select GeneReviews, then Titles)
Search: 1p36 deletion syndrome

Orphanet, European database
www.orpha.net 
Search: monosomy 1p36

Unique, a British database containing many chromosome disorders
www.rarechromo.org/html/home.asp 
Search: 1p36 deletion

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is senior physician Britt-Marie Anderlid, Astrid Lindgren Children’s Hospital, Stockholm, Sweden.

The relevant organizations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2013-12-27
Version: 3.0
Publication date of the Swedish version: 2013-10-22

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden, tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se

 

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This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.