What is Genomic Imprinting?

Patient Presentation
A 17-month-old male came to the emergency room with emesis and diarrhea for 1 day. His older sister had had similar problems 3 days before but after 36 hours improved. He had emesis three times of stomach contents. He had diarrhea multiple times of brown watery stool that leaked out his diaper twice. There was no blood or mucous in either fluid. He was afebrile. He was drinking small amounts of oral rehydration solution but had not had a wet diaper for 6-8 hours. His past medical history was significant for Silver-Russell syndrome that was diagnosed after birth because of being small for gestational age. He had postnatal growth retardation and was followed closely by gastroenterology. He had required a nasogastric feeding tube for a few months but he had stopped it 9 months ago and currently was growing at the 1st percentile. He saw multiple other services for his overall care, and had been hospitalized for dehydration or feeding difficulties twice in the past. The family history was negative for any genetic or neurological diseases. The review of systems was otherwise normal.

The pertinent physical exam showed a very tired-appearing, small, thin male sitting in his mother’s lap. His weight was down 680 grams from a clinic visit earlier in the week. He had triangular face with a prominent forehead and slightly low-set ears. His mucous membranes were slightly tacky and his capillary refill was 3+ seconds. HEENT examination was otherwise normal as were his heart and lungs. His abdomen showed increased bowel sounds without pain or guarding. Extremities showed a short male with thin musculature.

The diagnosis of a patient with gastroenteritis in the setting of Silver-Russell syndrome was made. Fluid resuscitation was given in the emergency room, but the patient refused to drink and continued to have emesis and diarrhea and so he was admitted. The patient’s clinical course revealed that the emesis and diarrhea resolved by day 2, but the patient was refusing to drink enough. Nutritional services, speech therapy and gastroenterology continued to work with the family and by Day 5 of admission he was taking his usual feedings and was discharged.

Silver-Russell syndrome (SRS) is a rare genetic syndrome first characterized by Silver in 1953 and Russell in 1954. Patients with SRS have characteristic growth patterns and clinical findings, although within an individual patient there are phenotypical differences. Patients are born small-for-gestational age (SGA) but have a relative macrocephaly. There is postnatal growth failure and difficulty feeding, with a very low body mass index. Body asymmetry (e.g. hemihypertrophy) and facial features (i.e. protruding forehead, triangular facies, micrognathia, dental anomalies, downturned mouth corners, and ear anomalies) are characteristic features.

Patients need multidisciplinary specialist care. SGA and feeding difficulties make patients often difficult to manage. Patients have lower muscle mass and excess calories quickly go to excess fat mass if patients are overfed. Gastroenterology, nutrition, speech therapy and psychology often manage these problems. Short stature can be marked (< 3 standard deviations below adult height) and recombinant growth hormone is used for treatment. Body asymmetry may need surgical treatment. Facial malformations can lead to dental, speech and otolaryngological problems that need to be addressed. Data on cognitive development is small, but if developmental or intellectual disabilities are identified they also need multimodal treatment.

Learning Point
Genomic imprinting is an epigenetic modification process, which allows a gene to be expressed in a single allelic, parent-of-origin specific manner. The imprinting occurs in gene clusters that are differentially methylated in both DNA and histones. These epigenetic methylated marks “…are acquired during gametogenesis, and normal embryo development is dependent on their maintenance after fertilization and during embryogensis.” This methylation process does not alter the gene sequence and is inherited independent of classic Mendelian inheritance. Imprinted genes control growth, development and metabolism. More than 100 imprinted genes have been identified in mice. About half of these are conserved in humans.

SRS generally is considered a sporadic inheritance, but there are some families where recessive, dominant or X-linked have occurred. Recurrence risk is considered low, but appropriate genetic counseling is important. Imprinting on chromosomes 7, 11, 15 and 17 have been recognized.

Currently known human imprinting disorders include:

  • Angelman syndrome
  • Beckwith-Wiedemann syndrome
  • Kagami-Ogata syndrome
  • Maternal uniparental disomy of chromosome 20 syndrome
  • Precocious puberty syndrome
  • Prader-Willi syndrome
  • Pseudohypoparthyroidism Type Ib
  • Silver-Russell syndrome
  • Transient neonatal Diabetes Mellitis 1
  • Temple syndrome

Imprinting in one area of chromosome 11 appears to cause some cases of SRS if transmitted maternally, but causes some cases of Beckwith-Wiedemann syndrome if transmitted paternally.

Questions for Further Discussion
1. What are indications for genetic counseling?
2. What support organizations for rare disorders are available locally or nationally?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.
Information prescriptions for patients can be found at MedlinePlus for these topics: Rare Diseases and Genetic Disorders.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Silver HK, Kiyasu W, George J, Deamer WC. Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins. Pediatrics. 1953 Oct;12(4):368-76.

Russell A. A syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples). Proc R Soc Med. 1954 Dec;47(12):1040-4.

Eggermann T. Russell-Silver syndrome. Am J Med Genet C Semin Med Genet. 2010 Aug 15;154C(3):355-64.

Ishida M. New developments in Silver-Russell syndrome and implications for clinical practice. Epigenomics. 2016 Apr;8(4):563-80.

Giabicani E, Netchine I, Brioude F. New clinical and molecular insights into Silver-Russell syndrome. Curr Opin Pediatr. 2016 Aug;28(4):529-35.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa