Clinical Diagnosis

The diagnosis of 1p36 deletion syndrome is suggested by the characteristic facial appearance, hypotonia, psychomotor retardation, and poor/absent speech and is confirmed by detection of a deletion of the most distal band of the short arm of chromosome 1 (1p36).

Typical facial features. The facial appearance of individuals with 1p36 deletion syndrome remains easily recognizable over time [Battaglia et al 2008], representing a hallmark of the condition [Battaglia 2005] (see figures). Facial features include straight eyebrows, deep-set eyes, midface hypoplasia, broad and flat nasal root/bridge, long philtrum, and pointed chin. Other craniofacial features are microcephaly, brachycephaly, epicanthal folds, large (>3 cm at birth) and late-closing anterior fontanel, and posteriorly rotated, low-set, abnormally formed ears [Shapira et al 1997, Heilstedt et al 2003b, Battaglia et al 2008].

Figure

Figures. Two unrelated children showing microbrachycephaly, straight eyebrows, deep-set eyes, broad/flat nasal bridge, midface hypoplasia, elongated philtrum, pointed chin, and hypotonic face.

A. 9.5-year-old girl

B. (more...)

Developmental delay/intellectual disability of variable degree is present in all. Generalized hypotonia is observed in 95% of individuals [Battaglia et al 2008].

Testing

Cytogenetic analysis. The four classes of rearrangements identified in individuals with monosomy 1p36 are shown in Table 1 [Heilstedt et al 2003b, Gajecka et al 2007]:

Table

Table 1. Chromosome Abnormalities Seen in 1p36 Deletion Syndrome

• An apparently "pure" terminal deletion

• Interstitial deletion

• More complex rearrangements including more than one deletion or deletions with duplications, triplications, insertions, and/or inversions

• Derivative chromosome 1 resulting from an unbalanced translocation

Note: (1) No common breakpoint or deletion size is present in individuals with monosomy 1p36. (2) Determining whether a cytogenetically visible deletion is a true terminal deletion or a more complex rearrangement may be accomplished using specialized molecular cytogenetic techniques (see Molecular Genetic Testing).

Molecular Genetic Testing

Genes. Deletion of genes in the 1p36 critical region is the only known cause of 1p36 deletion syndrome.

Clinical testing

• FISH. FISH using at least two subtelomeric region-specific probes (Vysis 1p subtel probe, Vysis p58 probe; D1Z2 Oncor probe or CEB108/T7) can identify parental rearrangements and may detect terminal and interstitial deletions and derivative chromosomes.

• Array GH (array-based genomic hybridization). Use of commercially available microarrays detects DNA copy-number changes in 1p36 deletion syndrome.

Note: (1) Subtelomere FISH detects the presence/absence of the two probes used; thus, FISH (a) cannot detect an interstitial deletion proximal to the probes; (b) cannot distinguish between a "true" terminal deletion and a more complex rearrangement; or (c) cannot define the extent of the deletion. However, array GH has the potential to do all three. (2) Although MLPA is clinically available, it is not a recommended method for detection of deletions of these sizes.

Table 2. Summary of Molecular Genetic Testing Used in 1p36 Deletion Syndrome

Test Method 1	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
Cytogenetic analysis 2	Deletion of 1p36 >5 Mb 3	~25%	Clinical
FISH 4	Deletion of 1p36 >100 kb 3	>95%	Clinical
Array GH 5		>95%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

Mb = 10⁶ DNA base pairs; kb = 10³ DNA base pairs

1. Although MLPA is clinically available, it is not a recommended method of detection of deletions of these sizes.

2. Conventional G-banded cytogenetic studies (routine and high-resolution)

3. Deletions greater than 5 Mb occur at approximately the same frequency as deletions smaller than 5 Mb.

4. Using at least two subtelomeric region-specific probes (1p subtel and p58 Vysis probes; D1Z2 Oncor probe or CEB108/T7)

5. Terminal deletions, interstitial deletions, complex rearrangements, and derivative chromosomes can potentially be detected by array GH.

Testing Strategy

Establish the diagnosis in a proband. It is appropriate to test any individual suspected of having 1p36 deletion syndrome as follows:

• Conventional cytogenetic studies to detect large deletions (i.e., >5 Mb) and more complex cytogenetic rearrangements (unbalanced chromosome translocations)

• FISH with at least two subtelomeric region-specific probes (Vysis 1p subtel probe, Vysis p58 probe; D1Z2 Oncor probe or CEB108/T7) to detect unbalanced translocations and to identify parental chromosome rearrangements

• Array GH to detect smaller deletions (i.e., <5 Mb) or interstitial deletions or complex rearrangements

Prenatal diagnosis for at-risk pregnancies requires prior confirmation of the diagnosis of 1p36 deletion syndrome in the proband and/or balanced status of a parent.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Natural History

The frequencies of the major clinical findings associated with 1p36 deletion syndrome are summarized in Table 3.

Intellectual disability. Developmental delay/intellectual disability is hallmarks of the syndrome. Battaglia et al [2008] found that 25% of affected individuals can walk alone, with a broad-based gait, by age two to seven years. Approximately 90% have severe to profound intellectual disability, whereas 10% have mild to moderate cognitive impairment. Expressive language is absent in 75% and limited to a few isolated words or at the level of first word associations in the remainder. Comprehension seems to be limited to a specific context. Intention to communicate, limited in early years, tends to improve over time, with extension of the gesture repertoire.

Behavior disorders, present in 50%, include poor social interaction, temper tantrums, self-biting of hands and wrists, a number of stereotypes, and, less frequently, hyperphagia.

Central nervous system defects, present in 88% of affected individuals, mainly include dilatation of the lateral ventricles and subarachnoid spaces; cortical atrophy; diffuse brain atrophy; and hypoplasia, thinning, and total or partial broadness of the corpus callosum. Other reported anomalies are delay in myelination, multifocal hyperintensity areas in the white matter [Battaglia et al 2008], and periventricular nodular heterotopia [Neal et al 2006].

Seizures occur in 44% to 58% of individuals with 1p36 deletion syndrome [Heilstedt et al 2001, Heilstedt et al 2003b, Bahi-Buisson et al 2008, Battaglia et al 2008]. Age at onset ranges from four days to two years, eight months. First seizures are either generalized (tonic, tonic-clonic, clonic, myoclonic) or partial (simple or complex). Almost 20% of all persons with the disorder have infantile spasms associated with hypsarrhythmia on EEG. Infantile spasms may either be the presenting seizure type or may follow other seizure types. Most seizure types are well controlled by standard pharmacotherapy. However, in one series [Bahi-Buisson et al 2008] nearly one-third of persons developed drug-resistant epilepsy.

A variety of EEG abnormalities are present in nearly all affected individuals [Heilstedt et al 2001, Bahi-Buisson et al 2008, Battaglia et al 2008].

Feeding difficulties may be caused by hypotonia and/or oral facial clefts with related difficulty in sucking, poorly coordinated swallow with consequent aspiration, and/or gastroesophageal reflux and vomiting. Mild to severe oropharyngeal dysphagia has been observed on swallow studies in 72% of individuals [Heilstedt et al 2003b].

Congenital heart defects are noted in 43% to 71% of individuals. Structural heart defects reported are (in order of frequency) atrial and ventricular septal defects, valvular anomalies, patent ductus arteriousus, tetralogy of Fallot, coarctation of the aorta, infundibular stenosis of the right ventricle, and Ebstein anomaly [Heilstedt et al 2003b, Battaglia et al 2008]. Twenty-seven percent had a history of cardiomyopathy in infancy and childhood. Cardiomyopathy was of the non-compaction type in 23% and tended to improve over time [Battaglia et al 2008].

Opthalmologic abnormalities Strabismus, nystagmus, refractive errors, and visual inattention are the most common ophthalmic manifestations of 1p36 deletion syndrome [Heilstedt et al 2003b, Battaglia et al 2008]. Cataract, retinal albinism, and optic nerve coloboma have occasionally been observed [Battaglia et al 2008].

Skeletal anomalies found in 40% of individuals with 1p36 deletion syndrome [Battaglia et al 2008] include delayed bone age, scoliosis, rib anomalies, and lower-limb asymmetry.

Hearing loss, mostly of the sensorineural type, can be detected in 47% to 82% of individuals with 1p36 deletion syndrome [Heilstedt et al 2003b, Battaglia et al 2008].

Genitourinary malformations can be seen in 22% of affected individuals and include unilateral renal pelvis with hydronephrosis of the upper pole, kidney ectopia with right kidney cyst, and unilateral pelvic ectasia [Battaglia et al 2008].

Cryptorchidism, hypospadias, scrotal hypoplasia, and micropenis are seen in a minority of males [Battaglia et al 2008].

Small labia minora and small clitoris, labia majora hypertrophy, and uterine hypoplasia have been reported in females [Battaglia et al 2008].

Hypothyroidism has been reported in 15% to 20% of persons of varied ages with deletion 1p36 syndrome in whom TSH and T4 levels were studied [Heilstedt et al 2003b, Battaglia et al 2008].

Other. Other abnormalities reported in a few individuals with 1p36 deletion syndrome include the following:

• Telangiectatic skin lesions and hyperpigmented macules [Keppler-Noreuil et al 1995]

• Polydactyly [Keppler-Noreuil et al 1995]

• Congenital spinal stenosis [Reish et al 1995]

• Congenital fiber type disproportion myopathy [Okamoto et al 2002]

• Redundant skin on the nape of the neck [Wang & Chen 2004]

• Intestinal malrotation and annular pancreas [Minami et al 2005]

• Hypertrophic pyloric stenosis

• Anteriorly placed or imperforate anus, hooked or bilobed gallbladder, and small spleen [Battaglia et al 2008]

• Neuroblastoma (in three individuals) [Laureys et al 1990, Biegel et al 1993, Anderson et al 2001]

• Pemphigus vulgaris (in one individual) [Halpern et al 2006]

Genotype-Phenotype Correlations

To explain the phenotypic variability of 1p36 deletion syndrome, investigators have searched for correlations between size of the 1p deletion and severity of clinical manifestations.

Wu et al [1999] and Heilstedt et al [2003b] suggested a complete genotype-phenotype correlation, identifying the critical regions for certain features and considering 1p36 deletion syndrome as a contiguous gene deletion syndrome. However, Gajecka et al [2007] found no correlation between deletion size and number of observed clinical features in a large cohort; even individuals with small (<3 Mb) deletions of 1p36 presented with most of the features commonly associated with the syndrome.

Redon et al [2005] hypothesized that the features associated with 1p36 deletion syndrome may result from a position effect rather than a contiguous gene deletion syndrome.

Prevalence

The prevalence of 1p36 deletion syndrome is estimated at between 1:5,000 and 1:10,000 births, with a 2:1 female to male ratio [Shapira et al 1997, Slavotinek et al 1999, Heilstedt et al 2003a, Battaglia et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with 1p36 deletion syndrome, the following evaluations are recommended:

• Measurements of growth parameters and plotting on standard growth charts
  Note: No growth charts are available specifically for 1p36 deletion syndrome.

• Physical and neurologic examination

• Evaluation of cognitive, language, and motor development and social skills

• Examination of the heart (auscultation, electrocardiogram, echocardiography) in infancy

• Waking/sleeping video-EEG-polygraphic studies (mainly in infancy) to detect infantile spasms with hypsarrhythmia

• Evaluation for feeding problems and gastroesophageal reflux with referral to a dysphagia team

• Ophthalmology consultation in infancy even in the absence of overt anomalies

• Physical examination for skeletal anomalies (e.g., scoliosis, lower-limb asymmetry); if anomalies are present, referral for orthopedic and physical therapy evaluation

• Comprehensive otolaryngologic evaluation and audiologic screening (brainstem auditory evoked responses) as early as possible to allow appropriate interventions

• Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies

• Periodic thyroid function screening

Treatment of Manifestations

Intellectual disability. Enrollment in a personalized rehabilitation program with attention to motor development, cognition, communication, and social skills is appropriate [Battaglia et al 2008]. Use of sign language enhances communication skills and does not inhibit the appearance of speech. Early intervention and, later, appropriate school placement are essential.

Seizures. Up to 25% of persons with 1p36 deletion syndrome develop infantile spasms associated with a hypsarrhythmic EEG, which are responsive to ACTH.

In most individuals, all seizure types are well controlled by standard antiepileptic drugs (AEDs), provided that the first-choice drug is started as early as possible.

Feeding difficulties. Feeding therapy with attention to oral motor skills is appropriate. Special feeding techniques or devices, e.g., the "Haberman feeder," can be used for feeding a hypotonic infant/child without a cleft palate or those with an unrepaired cleft palate. Gavage feeding is recommended for those with poorly coordinated swallow. Gastroesophageal reflux should be addressed in a standard manner. In one study, a few individuals with 1p36 deletion syndrome were managed with gastrostomy [Heilstedt et al 2003b].

Congenital heart defects are usually not complex and are amenable to repair. "Non-compaction" cardiomyopathy responds well to the standard pharmacotherapy (e.g., furosemide, captopril, digoxin) [Battaglia et al 2008].

Ophthalmologic abnormalities are treated in the standard manner. Visual inattentiveness, reported in up to 64% of individuals with 1p36 deletion syndrome, can be treated with an appropriate rehabilitation program [Bolognini et al 2005, Battaglia et al 2008].

Skeletal abnormalities (e.g., scoliosis, lower-limb asymmetry) need to be addressed on an individual basis. Early treatment (both physical therapy and surgery) is suggested.

Hearing loss is treated with a trial of hearing aids.

Other. Structural anomalies (e.g., gastrointestinal, renal) should be addressed in a standard manner. Hypothyroidism is treated in a standard manner.

Surveillance

Systematic follow-up allows for adjustment of rehabilitation and treatment as skills improve or deteriorate and medical needs change [Battaglia et al 2008].

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

1p36 deletion syndrome can be the result of an inherited or de novo chromosome abnormality.

Risk to Family Members

Parents of a proband

• The parents of a proband with 1p36 deletion syndrome are unaffected but may carry a balanced rearrangement involving 1p36 (see Table 1).

• Sixty percent of de novo deletions occur on the maternally derived chromosome

• In approximately one-third of individuals with a derivative chromosome 1, the derivative chromosome 1 results from malsegregation of a balanced parental translocation.

• Parents of individuals with 1p36 deletion syndrome should have cytogenetic analysis looking for a translocation involving 1p36. Array GH would not be recommended for this as the rearrangement would be expected to be balanced, and thus not detected.

• Subtelomeric analysis of both parents of a proband with an apparently de novo deletion is appropriate to detect the presence of a cryptic balanced translocation involving chromosome 1 in a parent [Heilstedt et al 2003b].

Sibs of a proband

• The risk to the sibs of a proband depends on the genetic status of the parents.

• If the deletion in the proband is de novo, the risk to the sibs of a proband is the same as the general population risk.

• If a parent is a balanced translocation carrier, the risk to sibs of being affected with 1p monosomy (i.e., 1p36 deletion syndrome) or 1p trisomy is increased over the general population risk.

Offspring of a proband. No individual with 1p36 deletion syndrome is known to have reproduced.

Other family members of a proband. If a parent is found to carry a chromosome rearrangement, his or her family members are also at risk of carrying the rearrangement.

Carrier Detection

If a parent of the proband is found to have a balanced chromosome rearrangement, at-risk family members can be tested by the method used to identify the rearrangement in the parent (i.e., chromosome analysis or subtelomeric FISH analysis).

Related Genetic Counseling Issues

Specific counseling issues. Specific empiric risks for translocations involving 1p and another chromosome are unknown.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are known to be or at risk of being carriers of a chromosome rearrangement.

Prenatal Testing

High-risk pregnancy. Prenatal testing is possible for families who have had a child with 1p36 deletion syndrome and in families in which one parent is known to be a carrier of a chromosome rearrangement. Cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15-18 weeks' gestation can be analyzed by a combination of cytogenetic methods (G-banding, FISH, and whole chromosome painting) depending on the specific findings in the proband and parent.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for couples at risk of having a pregnancy with 1p36 deletion syndrome caused by inherited chromosome rearrangement. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

No genes have been conclusively determined to be causative for any of the clinical features associated with 1p36 deletion syndrome.

Literature Cited

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Revision History

• 1 February 2008 (me) Review posted to live Web site

• 24 August 2007 (ab) Original submission