Isochromosome 18p syndrome (Tetrasomy 18p)
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A young child presents with global developmental delay, microcephaly, characteristic facies, and recurrent infections. Karyotype shows a small supernumerary marker chromosome; FISH with an 18p probe confirms i(18p), giving four copies of 18p (tetrasomy 18p).
- Almost always de novo, with maternal origin in ~90%+ of cases (molecular studies)
- Mechanism: formation of an isochromosome at the centromere region. Two models are described, both producing the same end result of two 18p arms joined head-to-head as a single supernumerary marker:
- U-type exchange between sister chromatids near the centromere (favored by most molecular studies)
- Transverse misdivision of the centromere (perpendicular split of the centromere, rather than the normal longitudinal split between sister chromatids)
- A meaningful fraction arise post-zygotically, which is part of why tissue-mosaic presentations are common
- The i(18p) chromosome exists as an extra small marker alongside two normal chromosome 18s, yielding four copies (tetrasomy) of the entire short arm of 18 (genome dose = 4× for genes on 18p)
- Unlike classic nondisjunction trisomies (Down, Edwards), no robust maternal age effect has been demonstrated
- Neurodevelopmental:
- Intellectual disability (moderate to severe)
- Global developmental delay, especially expressive language
- Hypotonia in infancy → spasticity over time
- Seizures in ~25-40%
- Craniofacial:
- Microcephaly
- High forehead with frontal bossing
- Long, oval face
- Strabismus, ptosis
- High-arched palate, micrognathia
- Low-set ears
- Growth & feeding:
- Pre- and postnatal growth restriction
- Feeding difficulties, gastroesophageal reflux
- Other:
- Recurrent infections (variable immune dysfunction reported)
- Variable cardiac anomalies (PDA, VSD)
- Skeletal: scoliosis, kyphosis, joint contractures
- Genitourinary: cryptorchidism, renal anomalies
- Karyotype with G-banding identifies the supernumerary marker
- FISH with chromosome 18-specific probes (centromere + 18p subtelomeric) confirms i(18p) and excludes a different small marker
- Chromosomal microarray shows mosaic-appearing 18p gain (tetrasomy = 4 copies) and is increasingly the first-tier test
- Molecular evaluation can distinguish meiotic origin (informs recurrence counseling)
- No targeted therapy; care is multidisciplinary surveillance and support
- Developmental services: early intervention, physical/occupational/speech therapy, individualized education support
- Neurology for seizure management and monitoring the hypotonia-to-spasticity transition
- Surveillance for associated anomalies: echocardiogram (cardiac defects), spine imaging (scoliosis/kyphosis), feeding and reflux management, and orthopedic follow-up for contractures
- Other small supernumerary marker chromosomes (sSMCs): i(12p) (Pallister-Killian syndrome), i(18p) (this entity), idic(15), i(22q) (Cat eye syndrome)
- Edwards syndrome (full trisomy 18): different gene dosage (3× of whole 18, including 18q), markedly different phenotype with high mortality
- Recurrence risk after a de novo case is low (background population risk)
- Parental karyotypes are recommended in all cases to rule out a balanced rearrangement
- Prenatal diagnosis available for subsequent pregnancies if desired
Four short, two long. An i(18p) adds two extra copies of the 18p arm on top of the two on normal chromosomes 18, giving four copies of 18p but only two copies of 18q. That dosage pattern, extra short arm alone with normal 18q, is why Tetrasomy 18p is milder and more variable than full trisomy 18 (Edwards syndrome), which adds an entire third chromosome 18.