Clinical characteristics.

1p36 deletion syndrome is characterized by typical craniofacial features consisting of straight eyebrows, deeply set eyes, midface retrusion, wide and depressed nasal bridge, long philtrum, pointed chin, large, late-closing anterior fontanel (77%), microbrachycephaly (65%), epicanthal folds (50%), and posteriorly rotated, low-set, abnormal ears. Other characteristic findings include brachy/camptodactyly and short feet. Developmental delay/intellectual disability of variable degree are present in all, and hypotonia in 95%. Seizures occur in 44%-58% of affected individuals. Other findings include structural brain abnormalities (88%), congenital heart defects (71%), eye/vision problems (52%), hearing loss (47%), skeletal anomalies (41%), abnormalities of the external genitalia (25%), and renal abnormalities (22%).

Diagnosis/testing.

The diagnosis of 1p36 deletion syndrome is suggested by clinical findings and confirmed by detection of a deletion of the most distal band of the short arm of chromosome 1 (1p36). Conventional G-banded cytogenetic analysis, FISH, or chromosomal microarray (CMA) can all be used to detect deletions; however, the complexity of some deletions may be detected only by CMA.

Management.

Treatment of manifestations: Rehabilitation/educational program with attention to speech/communication, use of sign language, motor development, cognition, and social skills; ACTH for infantile spasms; routine antiepileptic drugs (AEDs) for other seizure types; special feeding techniques and/or devices including gastrostomy tube for feeding difficulties; standard pharmacotherapy for non-compaction cardiomyopathy; standard care for eye/vision problems, skeletal anomalies, hearing loss, hypothyroidism, and renal abnormalities.

Surveillance: Systematic follow up for adjustment of rehabilitation/education and medical treatment as needs change over time.

Genetic counseling.

1p36 deletion syndrome is caused by deletion of the 1p36 chromosome region by one of several genetic mechanisms. Approximately 52% of individuals with 1p36 deletion syndrome have a de novo terminal 1p36 deletion, approximately 29% have an interstitial deletion, approximately 12% have more complex chromosome rearrangements that may include more than one 1p36 deletion or a 1p36 deletion with a 1p36 duplication, and approximately 7% have a derivative chromosome 1 (in which the 1p telomeric region is replaced by another chromosome end). Risks to family members depend on the mechanism of origin of the deletion. Prenatal testing is possible for families who have had a child with 1p36 deletion syndrome or a family in which one parent is a known carrier of a chromosome rearrangement involving 1p36.

Clinical Diagnosis

The diagnosis of 1p36 deletion syndrome is suggested by the characteristic facial appearance, hypotonia, psychomotor retardation, and poor or 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 Figure 1). Facial features include straight eyebrows, deeply set eyes, midface retrusion, wide and depressed nasal 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 1.

Two unrelated children showing microbrachycephaly, straight eyebrows, deeply set eyes, wide and depressed nasal bridge, midface retrusion, elongated philtrum, pointed chin, and hypotonic face A. Girl age 9.5 years

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]:

• 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).

Table 1.

Chromosome Abnormalities Seen in 1p36 Deletion Syndrome

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	Chromosome Abnormality
	Terminal deletion	Interstitial deletion	Complex rearrangement 1	Derivative chromosome 2
Chromosome diagram
Proportion of 1p36 deletion syndrome	52%	29%	12%	7%

Heilstedt et al [2003b], Gajecka et al [2007]

1.

Including more than one deletion or deletions with duplications, triplications, insertions, and/or inversions affecting chromosome 1p36

2.

The 1p telomeric region is replaced by another chromosome end.

Testing Strategy

To confirm/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
• Deletion/duplication analysis by CMA to detect smaller deletions (i.e., <5 Mb) or interstitial deletions or complex rearrangements

Notes: (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, CMA has the potential to do all three. (2) MLPA, a type of deletion/duplication analysis, is not a recommended method for detection of deletions of these sizes.

Clinical Description

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

Intellectual disability. Developmental delay and intellectual disability are 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 stereotypies, 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 absence of the corpus callosum. Other reported anomalies are delay in myelination, multifocal hyperintensity areas in the white matter [Battaglia et al 2008], periventricular nodular heterotopia [Neal et al 2006, Descartes et al 2011], and polymicrogyria [Dobyns et al 2008].

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.

Of note, epileptic apneas can also occur in some children [Kanabar et al 2012]; and early infantile epileptic encephalopathy with suppression bursts (Ohtahara syndrome) has also been reported in an individual [Paciorkowski et al 2011].

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].

Ophthalmologic 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, anular pancreas, and anomalous arrangement of the pancreaticobiliary duct [Minami et al 2005, Kawashima et al 2011]
• Liver steatosis [Haimi et al 2011]
• Hypertrophic pyloric stenosis
• Anteriorly placed or imperforate anus, hooked or bilobed gallbladder, and small spleen [Battaglia et al 2008]
• Neuroblastoma (in 3 individuals) [Laureys et al 1990, Biegel et al 1993, Anderson et al 2001]
• Pemphigus vulgaris (in 1 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.

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 and needs 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 or at diagnosis 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 (brain stem 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
• Consultation with a clinical geneticist and/or genetic counselor

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; the spasms 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].

Evaluation 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 in the US and EU Clinical Trials Register in Europe 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.

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. CMA 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 should be the same as the general population risk. Of note, apparent germline mosaicism has been reported in one family [Gajecka et al 2010].
• 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 carries a chromosome rearrangement, his or her family members are also at risk of carrying the rearrangement.

Carrier Detection

If a parent of the proband has 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 and Preimplantation Genetic Testing

High-risk pregnancy. In families who have had a child with 1p36 deletion syndrome or in which one parent is known to be a carrier of a chromosome rearrangement, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic testing are possible.

Molecular Pathogenesis

No genes have been conclusively determined to be associated with the clinical features that characterize 1p36 deletion syndrome.

Literature Cited

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Author History

Agatino Battaglia, MD (2008-present)
Lisa G Shaffer, PhD, FACMG; Signature Genomic Laboratories (2008-2013)

Revision History

• 8 August 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population
• 6 June 2013 (me) Comprehensive update posted live
• 1 February 2008 (me) Review posted live
• 24 August 2007 (ab) Original submission