CHROMOSOME 18 CLINICAL RESEARCH CENTER

Chromosome 18 Clinical Management Guides

Tetrasomy 18p
Treatment and Surveillance

ICD-10 =Q93.2

These recommendations are inclusive of the entire population of people with Tetrasomy 18p. It should be noted that there is a great deal of variation among individuals with Tetrasomy 18p. Not all complications or concerns will be listed in this document. However, the recommendations contained here should be used as a baseline for monitoring and the health of individuals with Tetrasomy 18p.

Potential conditions in a neonate

  • Structural
    • Palate abnormality - 81%
    • Heart abnormalities -47% by Echo/ECG
    • Congenital orthopedic abnormalities-45%
    • Hernias-12%
    • Myelomeningocele-7%
  • Functional
    • Feeding problems – 83%
    • Respiratory distress – 31%
  • Biochemical
    • Jaundice - 57%

Initial evaluations after diagnosis

  • Ophthalmology
    • Strabismus –  75%
    • Refractive errors –  71%
  • Audiology / Otolaryngology
    • Hearing loss - 32%
    • Recurrent otitis media –  57%
  • Genitourinary
    • Cryptorchidism –  63%
    • Hypospadias – 7%
    • Urinary tract anomalies – 28%

Immediate Referrals to

Closely monitor and manage

  • Underweight (< 3rd percentile)
  • Endocrinology
    • Short stature (< 25th percentile)
    • Growth hormone deficiency
  • Orthopedics
    • Congenital hip dysplasia
    • Foot abnormalities
    • Decreased bone mineral density
Annual Screenings
  • Vision
  • Hearing

 
 
 
 

Potential conditions in a neonate

  • Structural
    • Palatal anomalies - 81%
      • High, arched or narrow
    • Cardiac abnormalities – 47% by Echo and ECG
      • Most common: PDA 17%, VSD 14%, PFO 7%, ASD 5%. None of these required surgery as most of these closed spontaneously
      • Other less occurred cardiac anomalies have included : hypoplastic transverse aortic arch; right ventricular hypertrophy; pulmonic stenosis; and valve abnormalities
    • Congenital orthopedic abnormalities – 45%
      • Club foot – 14%
      • Vertical talus – 5%
      • Metatarsus adductus – 5%
      • Rockerbottom feet – 5%
      • Hip dysplasia – 17%
    • Hernias (hiatal, inguinal, umbilical) – 12%
    • Myelomeningocele – 7%
  • Functional
    • Feeding problems – 83%
      • Due to hypotonia, high arched palate or gastroesophageal reflux
    • Respiratory distress – 31%
  • Biochemical
    • Jaundice – 57%

Initial evaluations after diagnosis:

  • Ophthalmology 
    • Strabismus – 75%
    • Esotropia – 17%
      • Accommodative – 30%
      • Infantile – 21%
      • Acquired non-accommodative – 8%
      • Intermittent – 8%
    • Esophoria –  4%
    • Intermittent exotropia – 4%
    • Refractive errors – 71%
      • Myopia –  17%
      • Hyperopia –  33%
      • Astigmatism – 25%
    • Anisometropia – 17%
  • Audiology / Otorhinolaryngology
    • Hearing loss - 32%
      • Conductive, sensorineural, and mixed hearing loss have all been reported
    • Recurrent otitis media – 57%
    • Small or narrow ear canals – 42%
    • Anisometropia - 17%
  • Genitourinary
    • Cryptorchidism –  63%
    • Hypospadias – 7%
    • Urinary tract anomalies – 28% (horseshoe kidney and bladder diverticuli, small kidney, renal cyst, hydronephrosis, vesicoureteral reflux varying degrees)
      • The actual incidence of kidney abnormalities may be higher than reported in the literature  as abdominal ultrasounds have not performed on all individuals

Immediate Referrals to:

  • Genetics
    • Referral to genetics is appropriate to review the condition, its management, and implications for other family members.
    • A minority of parents of children with tetrasomy 18p have a chromosome abnormality.
    • There have been case reports of parents with mosaicism or with some type of chromosome rearrangement.
  • Early intervention/developmental services
    • All children with chromosome 18 abnormalities have a significant risk for developmental delay and intellectual disabilities.  Prompt referral to a program the includes physical, occupational and speech therapy is important in order maximize their development.
    • 100% with tetrasomy 18p have developmental delay
    • 100% have muscle tone abnormalities that may benefit from physical therapy
    • 100% have intellectual disability, though the degree of severity varies.
  • Referral to Chromosome 18 Registry & Research Society
    • The Chromosome 18 Registry is a parent support organization that provides  family members with the opportunity to meet and learn from those who have gone before them.  These are complex conditions to manage even in the least affected children making the establishment of a network of support a crucial component for maximizing the affected child’s potential. The Registry has annual national and international conferences, regional get-togethers and social media outlets, all with programs for parents, siblings and affected  adults.  The Registry works closely with and financially supports the Chromosome 18 Clinical Research Center
  • Referral to the Chromosome 18 Clinical Research Center
    • The goal of the Chromosome 18 Clinical Research Center is to make the chromosome 18 abnormalities the first treatable chromosome abnormalities. Anyone with any chromosome 18 abnormality is eligible to enroll and encouraged to enroll. Once enrolled, participants have the opportunity to  be involved in longitudinal studies of developmental progress, and when available, other studies  that could include surveys or treatment trials. Families enrolled in the Research Center will also be the first to know new information about the conditions when it becomes available. Enrollment is a key part of proactive clinical management.

Closely monitor and manage:

  • Failure to thrive/growth failure
    • Underweight (<3rd%) – 19%
    • Weight gain
      • Due to their hypotonia, feeding may be more difficult for an infant with Tetrasomy 18p. In addition, many affected children have gastroesophageal reflux, which increases not only their risk for aspiration, but also for pain, discomfort or emesis after feeding.  Children <3 years who are failing to meet expected rates of weight gain should be evaluated for reflux and potentially for placement of a feeding tube. In addition, there have been a handful of individuals with Tetrasomy 18p that have been diagnosed with eosinophilic esophagitis.
  • Endocrinology
    • Short stature (<25%) – 52%
    • Failed  two growth hormone provocative tests  - 19%
    • IGF1 and IGFBP3 are not definitive tests for GH deficiency in these children
    • Children that are failing to grow linearly (length or height) at expected rates for age and sex should be tested using growth hormone stimulation  (provocative) testing. This testing is typical performed by a pediatric endocrinologist.
    • Thyroid and gonadotropin testing was normal in all participants but one individual (12 years old) is on thyroid medication because of hypothyroidism.
    • Type 2 Diabetes - 1%
  • Otorhinolaryngology
    • Recurrent otitis media – 57% .
      • It is important to monitor hearing and treat ear infections quickly to avoid hearing loss and delayed speech development.
    • Hearing loss – 32%
      • Conductive - 29%
      • Sensorineural - 12%
      • Mixed hearing loss - 7%
      • Unspecified - 8%
  • Gastroenterology
    • Chronic constipation  - 76%
      • This is a chronic issue and failure to successfully manage bowel issues has resulted in failure to ever achieve bowel continence and has even resulted in the need for ileostomy. There are no data indicating neuogenic bowel disease but the serious and chronic nature of the constipation resembles such a condition
    • GE reflux – 36%
    • Hernias (hiatal, inguinal, umbilicial) - 12%
    • Pyloric stenosis - 5%
    • Eosinophilic esophagitis – only a few individuals have been definitively diagnosed by endoscopy, however a significant proportion have some symptomology.
  • Immunology/Rheumatology
    • Atopic disorders
      • Food allergies – 33%
      • Asthma – 9%
      • Hay fever – 45%
      • Eczema – 21%
    • IgA deficiency - 18%
    • Arthritis - 5%
    • Celiac disease in one individual
    • Eosinophilic esophagitis – only a few have been definitively diagnosed by endoscopy
  • Orthopedics
    • Orthopedic abnormalities – 69%
      • Scoliosis or kyphosis  - 53%
      • Pes planus– 49%
      • Hip dysplasia - 17%
      • Club foot - 14%
      • Metatarsus adductus 5%, Rocker bottom feet 5%, Vertical talus 5%
    • Low BMD (this is a new finding under investigation – so far 100% of those assessed down to the age of 4 years have low bone mineral density.)
  • Development
    • The average full scale IQ score is 48
    • Cognitive abilities vary significantly;
      • 37% in the mild range
      • 37% moderate
      • 26% in the severe to profound range
    • Mean age when: walking independently at 33 months, saying single words at 28 months and 2-3 word phrases at 66 months
    • Developmental milestones are delayed compared to a typical population (see O’Donnell et al., 2015).
  • Dental
    • Dental crowding - 19%
  • Neurology
    • Brain MRI variants - 58%
      • White matter changes (hyperintense /hypointense signal areas; low volume of white matter; hypomyelination) ~30%
      • Corpus callosum abnormalities (thin/hypoplastic)– 28%
      • Ventricular system enlargement – 23%
      • Choroid plexus cyst – 9%
      • Chiari malformation – 7%
      • Periventricular Leukomalacia – 7%
      • Iron deposition – 2%
      • Mastoiditis – 2%
      • There are other MRI changes in single individuals like: lipoma; extra fluid surrounding the brain; small pineal cyst
    • Seizures - 54%(most of the seizures were caused by fever/illness 33%, whereas 23% had no apparent trigger)
    • Microcephaly - 74%
    • Ptosis - 13%
    • Myselomeningocele - 7%
    • Abnormal muscle tone – 98%
      • Hypotonia – 50%
      • Hypertonia – 19%
      • Mixed tone – 28%
  • Behavioral/ mood changes
    • Children - Problems with functional communication (97%), activities of daily living (91%), attention problems (61%), hyperactivity (54%)
    • Adults – Problems with functional communication (62%), activities of daily living (62%), hyperactivity (54%)
  • Executive Function
    • Children – Problems with working memory (95%), task monitoring (90%), inhibiting (85%), initiating (70%), planning/organizing (70%), shifting (60%), emotional control (50%)
    • Adults – Problems with working memory (93%), initiating (71%), inhibiting (64%), shifting (64%), planning/organizing (64%), task monitoring (50%)
  • Social Impairment
    • Children and Adults – Problems with social cognition (91%), restricted interests and repetitive behaviors (91%), social awareness (82%), social communication (73%), social motivation (55%)
  • Early death
    • In general, individuals with Tetrasomy 18p are not medically fragile. In our cohort of 70 individuals with Tetrasomy 18p, only one participant has died. Although the cohort is relatively young with an average age of about 14 years.  The oldest participant is 50 years old. The one death was presumed to be from sudden cardiac arrest at age 13 years.
  • There is no  reason to think that they are at increased risk for surgical or anesthesia complications although they may need increased monitoring due to hypotonia.

References

Abeliovich D, Dagan J, Levy A, Steinberg A, Zlogogora J (1993). Isochromosome 18p in a mother and her child. Am J Med Genet 46: 391-393.

 

Boyle J, Sangha K, Dill F, Robinson WP, Young SL (2001). Grandmaternal origin of an isochromosome 18p present in two maternal half-sisters. Am J Med Genet 101:65-69.

 

O’Donnell L, Soileau BT, Sebold C, Gelfond J, Hale DE, Cody JD (2015). Tetrasomy 18p: Report of cognitive and behavioral characteristics. Am J Med Genet Part A 167A: 1474-1482.

 

Sebold C, Roeder E, Zimmerman M, Soileau B, Heard P, Carter E, Schatz M, White WA, Perry B, Reinker K, O’Donnell L, Lancaster J, Li J, Hasi M, Hill A, Pankratz L, Hale, DE, Cody JD (2010). Tetrasomy 18p: Report of the Molecular and Clinical Findings of 43 Individuals. Am J Med Genet Part A 152A: 2164-2172.

 

Soileau B, Hasi M, Sebold C, Hill A, O'Donnell L, Hale DE, Cody JD. Adults with Chromosome 18 Abnormalities. J Genet Couns. 2015 Aug;24(4):663-74

 

Takeda K, Okamura T, Hasegawa T (1989). Sibs with tetrasomy 18p born to a mother with trisomy 18p. J Med Genet 26: 195-197.