Competing Phenotypes Due to Multilocus Hypomethylation

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History (including chief complaint, history of present illness and relevant past and family medical history)

A male infant was born to a 27-year-old gravida 1 mother at 35 2/7 weeks gestation via cesarean section for breech presentation in the setting of preterm labor. The pregnancy was complicated by maternal obesity, gestational diabetes controlled with metformin, omphalocele and fetal intrauterine growth restriction. After an unremarkable delivery course, the infant was admitted to the neonatal intensive care unit for management of the omphalocele.

Physical examination findings (including vital signs)

The infant was average for gestational age for all parameters; birth weight was 50th percentile. Vital signs were within normal limits. Exam was notable for low set ears, small pit and tag on the left ear, prominent occiput, wide mouth and macroglossia. No murmur or respiratory distress. Omphalocele with bowel protruding into the umbilical cord. Overlapping toes.

Laboratory or Diagnostic imaging or Procedures

The infant remained euglycemic without increased glucose requirements. Echocardiogram was significant for a small mid-muscular ventricular septal defect. Renal and head ultrasounds were unremarkable.

The infant underwent surgical repair of the omphalocele on day of life five. Hospital course was complicated by prolonged time to oral feeding thought to be secondary to prematurity and macroglossia as well as low-normal growth velocity. Infant was discharged home on full oral feeds at 48 days of life.

Final Diagnosis

Methylation testing was recommended following genetics consultation. Testing revealed loss of methylation of both IC1 (38% methylated) and IC2 (0.78% methylated) on chromosome 11p15.5 consistent with a diagnosis of both Russell-Silver Syndrome (RSS) and Beckwith-Wiedemann Syndrome (BWS) respectively.


BWS is characterized by variable overgrowth such as macroglossia, hemihypertrophy and organomegaly as well as hypoglycemia and omphalocele. In contrast, RSS is associated with low birthweight, short stature and feeding difficulties. Both diseases originate from abnormally imprinted genes on chromosome 11p15 which that regulate fetal growth.  Hypomethylation of different domains leads to opposing phenotypes.  We describe a unique loss of methylation in two regions with clinical characteristics of both syndromes displayed our patient.

Chromosome 11p15 contains two main domains, each with their own imprinting control (IC) region.  The IC1 domain primarily is normally methylated on the paternally derived chromosome. Hypomethylation of IC1 can lead to increased activity H19, which restrains growth, and a loss of IGF2 activity, which normally promotes growth, resulting in RSS.

The IC2 domain is normally methylated on the maternally derived chromosome. Loss of methylation of the IC2 domain leads to silencing of CDKN1C which normally restrains cell growth and division, resulting in BWS. Loss-of-function mutations in CDKN1C can also cause the same phenotype. 

While multilocus loss of methylation has been reported in 9.5% of RSS patients and 24% of BWS patients, with 2.8% showing loss of methylation at both IC1 and IC2. An infant's dominant phenotype which is hypothesized to be determined by the region with greater loss of methylation, consistent with our infant's mixed presentation. Our case report emphasizes the importance of evaluating for other methylation disorders if one disorder is identified.

Tufts Children's Hospital at Tufts Medical Center
Tufts Children's Hospital at Tufts Medical Center
Tufts Children's Hospital at Tufts Medical Center

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