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Handbook of Genetic Counseling/1p36 Deletion Syndrome-2

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1p36 Deletion Syndrome

Introduction

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  • Mental retardation affects 2-3% of the population and chromosome abnormalities account for about 20% of cases
  • Improved techniques in cytogenetics (FISH) have helped to identify submicroscopic deletions at the cytogenetic level
  • Syndrome is characterized by distinct facial features, mental retardation, and delayed growth
  • This condition is likely a contiguous gene deletion syndrome
    • There is no uniform region of deletion but rather a spectrum of different deletion sizes with a common minimal region of deletion overlap
    • Genotype/phenotype comparisons can help researchers to start to define a region in which to search for candidate genes for specific features

Etiology of 1p36 deletion syndrome (monosomy 1p36)

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  • Caused by deletion of the most distal (telomeric) light band of the short arm of chromosome 1
  • Most clinical manifestations are probably caused by the absence of one copy of a dose-sensitive gene
  • Patients with a 1p36 deletion have different sized pieces of the chromosome missing and may result in phenotype variability
    • Mechanism causing chromosome breakage is unknown
    • Severity of associated disorders varies, but the physical features are very similar
    • Degree of MR and ability to acquire complex speech is somewhat dependent on deletion size
  • Most deletions affect the chromosome inherited from the mother (68%), but there doesn't seem to be differences in the clinical manifestations based on whether the deletion is on the paternal or maternal chromosome.
  • Those with paternally derived deletions tend to have larger deletions than those with maternally derived deletions

Prevalence

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  • Prevalence of this deletion is estimated to be 1 in 10,000 to as high as 1 in 5,000 (making it the most common terminal deletion)
  • Most cases result from sporadic deletions and are not inherited
  • 1p36 deletion syndrome is usually diagnosed through recognition of the symptoms and characteristics as well as lab testing.
    • This is done using high-resolution chromosome analysis or FISH with a chromosome 1-specific subtelomeric probe.
    • The deletion often doesn't show up clearly with standard cytogenetic banding techniques.

Characteristics

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  • Children with 1p36 deletion syndrome are all unique individuals, but do have some common characteristics.
  • Distinct facial features including:
    • Large anterior fontanel (~100% of patients)
    • Small and pointed chin (~80%)
    • Flat nasal bridge (~65%)
    • Clinodactyly and/or short fifth finger (~64%)
    • Low-set ears, ear asymmetry (~59%)
    • Thickened ear helices (~53%)
    • Small head
    • Deep-set eyes (~50%)
  • Most patients have mental retardation
  • Most patients have delayed growth (~85%) and/or difficulty gaining weight
    • Some have difficulty with sucking and swallowing while others may not grow well even though they eat well.
    • Some older children may become obese.
  • Most young children with 1p36 deletion syndrome have delayed development.
    • They sit up, walk and talk later than typical children.
  • Speech is severely affected with many patients learning only a few words
  • Other medical problems:
    • Hypotony (which may explain delayed motor skills) (seen in ~92%)
    • Hearing loss (~56%)
    • Seizures (~72%)
      • KCNAB2 is a voltage-gated K+ channel beta-subunit gene that has been localized to 1p36 and thought to be associated with the epilepsy phenotype of 1p36
    • Eye/vision problems (~75%)
    • Hypothyroidism
    • Increased risk for neuroblastoma
    • Heart defects (which have included cardiomyopathy, ductus arteriosus, tetralogy of Fallot, VSD)
    • Orofacial clefting abnormalities
      • SKI, a proto-oncogene located at distal 1p36.3 has been found to be deleted in a number of patients tested and may contribute to facial clefting seen in this syndrome
      • SKI overexpression has suggested that the gene is involved in neural tube development and muscle differentiations.

Recurrence Risk for next pregnancy

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  • The majority of patients with 1p36 deletion syndrome are isolated cases resulting from a de novo deletion. There have been reports of patients with 1p36 deletion syndrome whose parents have a balanced translocation.
  • Parents should be tested for chromosomal rearrangements because about 6% of parents with an affected child have a balanced translocation
  • Translocation increases the chances of having another child with a 1p36 deletion.
    • If no translocation is found the chances of having another child with a 1p36 deletion are very small

Prenatal Diagnosis

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  • In 1999 a case was reported in which a 1p36 deletion in a fetus was detected when an amniocentesis was performed due to detection of multiple malformations on ultrasound
  • Another case was picked up prenatally because of the presence of elevated maternal serum alpha-fetoprotein (no abnormal sign seen on ultrasound)
  • Another was diagnosed prenatally because the mother was known to have a balanced translocation between the short arms of chromosome 1 and 20 that was picked up after their first child had inherited an unbalanced product. (no abnormal sign seen on ultrasound)

Medical Treatment

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  • Seizures can usually be controlled with medication
  • Medical interventions and feeding therapy may be needed to manage feeding issues
  • Early Intervention for developmental delay
  • Surgery may be necessary to correct heart defects, cleft lip, cleft palate if present
  • Physical examinations should involve palpating the abdomen for lumps which might be neuroblastomas
  • There are no clear indications on whether they should continue to be followed by a cardiologist or whether the cardiomyopathy is limited to a congenital form.

Psychosocial Issues

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  • Initially parents may experience denial about how severe the developmental delay and mental retardation will be
  • Blaming of self or partner may occur
  • Stress of having a child with developmental delays and mental retardation
  • Stress associated with having a child with serious medical problems especially if they have heart malformations or seizures
  • Time commitment involved with early intervention services (OT, PT, speech therapy)

Patient Resources

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  • 1p36 Deletion Syndrome [1]
  • Chromosome Deletion Outreach [2]
  • MUMS [3]

References

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  • Colmenares, C., et al. Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski -/- mice. Nature Genetics 30(1), 106-109, Jan 2002.
  • Faivre, L. et al. Prenatal Detection of a 1p36 Deletion in a Fetus with Multiple Malformations and a Review of the Literature. Prenatal Diagnosis. 19:49-53, 1999.
  • Heilstedt, H.A. et al. Loss of the Potassium Channel B-subunit gene, KCNAB2, Is Associated with Epilepsy in Patients with 1p36 Deletion Syndrome. Epilepsia. 42(9): 1103-1111, 2001.
  • Shaffer, L.G. and Heilstedt, H.A. Terminal Deletion of 1p36. The Lancet Supplement 358: 89, 2001.
  • Shapira, Stuart, et al. Chromosome 1p36 Deletions: The Clinical Phenotype and Molecular Characterization of a Common Newly Delineated Syndrome. American Journal of Human Genetics 61: 642-650, 1997.
  • Slavotinek, Anne, Lisa G. Shaffer, Stuart K Sharpira. Monosomy 1p36. Journal of Medical Genetics 36: 657-663, 1999.

Notes

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The information for this outline was last updated in June of 2002.

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