Random Dermatology MCQ - Russell Silver syndrome

A 3-year-old child is evaluated for severe prenatal and postnatal growth failure (length and weight <3rd percentile). On examination, the child has a relatively large head (pseudohydrocephalus), a triangular face with a prominent forehead and small chin, and asymmetry of the lower limbs. The fifth fingers show clinodactyly. The mother reports the child required frequent feeding as an infant due to recurrent hypoglycemia. What is the most likely underlying epigenetic abnormality and the associated critical management focus in infancy?

A. Hypermethylation of the H19/IGF2 imprinting control region (ICR1) on chromosome 11p15; management focuses on ensuring adequate caloric intake and preventing hypoglycemia.
B. Mutation in the NSD1 gene; management focuses on cardiac surveillance.
C. Deletion on chromosome 15q11-13 (maternal); management focuses on behavioral and feeding support.
D. Trisomy of chromosome 21; management focuses on cardiac and thyroid screening.
E. Mutation in the FBN1 gene; management focuses on aortic imaging.

Correct Answer: A. Hypermethylation of the H19/IGF2 imprinting control region (ICR1) on chromosome 11p15; management focuses on ensuring adequate caloric intake and preventing hypoglycemia.

Answer and Explanation

The correct answer is A. This question describes the classic features of Russell-Silver syndrome (RSS). The key clues are: severe intrauterine and postnatal growth restriction with preservation of head circumference (leading to relative macrocephaly or pseudohydrocephalus), characteristic facial features (triangular face, prominent forehead, small chin), body asymmetry (hemihypoplasia), and a history of neonatal/infantile hypoglycemia. The most common molecular abnormality (in ~60% of cases) is hypomethylation of the paternal imprinting center region 1 (ICR1) on chromosome 11p15. This disrupts the normal expression of IGF2 (a fetal growth promoter), leading to impaired growth. The cornerstone of early management is nutritional support to prevent hypoglycemia and optimize growth.

Why the Other Options are Incorrect:

• B. Mutation in the NSD1 gene: This causes Sotos syndrome, characterized by overgrowth (prenatal and postnatal), macrocephaly, and learning disability, which is the opposite phenotypic pattern to RSS.

• C. Deletion on chromosome 15q11-13 (maternal): This causes Prader-Willi syndrome, which features neonatal hypotonia and poor feeding followed by hyperphagia and obesity, not the persistent growth failure, triangular facies, and asymmetry of RSS.

• D. Trisomy of chromosome 21: This causes Down syndrome, characterized by distinct dysmorphic features (e.g., upslanting palpebral fissures, single palmar crease), congenital heart defects, and intellectual disability, not the specific growth pattern of RSS.

• E. Mutation in the FBN1 gene: This causes Marfan syndrome, characterized by tall stature, arachnodactyly, and aortic root dilation, which is antithetical to RSS.

Additional High-Yield Information for Exams:

• Clinical Diagnostic Criteria (Netchine-Harbison Clinical Scoring System): A score of ≥4/6 suggests RSS:

  1. Small for Gestational Age (SGA)

  2. Postnatal growth failure

  3. Relative macrocephaly at birth

  4. Protruding forehead (body disproportion)

  5. Body asymmetry

  6. Feeding difficulties and/or low body mass index (BMI)

• Genetics: Genetically heterogeneous. Two main causes:

  1. 11p15 ICR1 Hypomethylation (~60%): Maternal uniparental disomy (UPD) of chromosome 7 is another, less common cause. This epigenetic disruption reduces IGF2 expression.

  2. The condition is usually sporadic.

• Clinical Features:

  • Growth: Persistent short stature. Catch-up growth is poor even with growth hormone therapy.

  • Endocrine/Metabolic: Hypoglycemia in infancy/childhood is common due to low muscle mass and poor feeding. Precocious puberty can occur, further limiting final height.

  • Skeletal: Clinodactyly, asymmetry (limb length discrepancy), scoliosis.

  • Other: Gastroesophageal reflux, severe constipation, speech and motor delays.

• Differential Diagnosis: Other causes of severe prenatal-onset growth restriction, such as 3-M syndrome (similar facies but no asymmetry), Mulibrey nanism, or primordial dwarfism syndromes.

• Associated Conditions & Prognosis:

  • Prognosis: Final adult height is markedly reduced. Intellectual development is typically normal, though learning disabilities may occur. Quality of life depends on management of feeding issues, hypoglycemia, and skeletal complications.

• Management & Rationale:

  • Rationale: Management is supportive and multidisciplinary, focusing on optimizing nutrition and growth, managing hypoglycemia, and addressing skeletal/developmental issues.

  • First-line/Critical Management in Infancy & Childhood:

    • Nutritional Support: High-calorie feeds, frequent small meals to prevent hypoglycemia. May require nasogastric or gastrostomy tube feeding.

    • Endocrine: Growth hormone (GH) therapy is used and can improve height velocity and body composition, but the response is often less robust than in other SGA conditions. Close monitoring for hypoglycemia is essential.

    • Orthopedic: Monitoring and treatment of limb length discrepancy (shoe lift, epiphysiodesis) and scoliosis.

  • Multidisciplinary Team: Involves endocrinology, gastroenterology/nutrition, orthopedics, and genetics.