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

 * Chromosome Deletion Outreach
 * MUMS