Handbook of Genetic Counseling/1p36 Deletion Syndrome-2

1p36 Deletion Syndrome

Introduction

• 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)

• 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

• 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

• 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

• 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

• 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

• 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

• 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

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

References

• 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

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