What genetic syndrome is characterized by a Trendelenburg sign, tall stature, flexibility, and precocious puberty in a pediatric female patient?

Marfan Syndrome

The constellation of Trendelenburg sign, tall stature, flexibility (joint hypermobility), and precocious puberty in a pediatric female patient most strongly suggests Marfan syndrome, though the precocious puberty is atypical and warrants investigation for alternative explanations or coexisting conditions. 1, 2

Clinical Reasoning

Core Features Matching Marfan Syndrome

Marfan syndrome is caused by mutations in the FBN1 gene and is characterized by tall stature, elongated extremities, and connective tissue abnormalities affecting multiple organ systems. 1 The key features in this case align as follows:

• Tall stature: This is a cardinal skeletal manifestation of Marfan syndrome, resulting from defective fibrillin-1 protein affecting connective tissue integrity 2, 3, 4

• Flexibility (joint hypermobility): Joint hypermobility rather than true inflammation is a common feature of Marfan syndrome and related connective tissue disorders 2

• Trendelenburg sign: This gait abnormality suggests hip instability or weakness, which can occur in Marfan syndrome due to protrusio acetabuli (assigned 2 points in the systemic score) or generalized connective tissue laxity affecting hip mechanics 2

The Precocious Puberty Discrepancy

Precocious puberty is NOT a recognized feature of Marfan syndrome. 1, 2, 5 In fact, the typical presentation would be the opposite—patients with Marfan syndrome often have delayed puberty or normal pubertal timing, not early puberty. This discrepancy requires careful consideration:

• If precocious puberty is truly present, investigate for coexisting endocrine pathology unrelated to Marfan syndrome 2
• Consider whether "precocious puberty" is being confused with tall stature for age, which can give the appearance of advanced development 2, 6

Diagnostic Approach

Apply the 2010 Revised Ghent Nosology criteria for diagnosis. 1, 2 The diagnosis requires:

• Aortic root dilation (Z-score ≥ +2) PLUS ectopia lentis, OR 2
• Aortic root dilation PLUS pathogenic FBN1 mutation, OR 2
• Aortic root dilation PLUS systemic score ≥7 points, OR 2
• Ectopia lentis PLUS FBN1 mutation previously associated with aortic disease 2

Systemic Score Calculation

Calculate points based on specific skeletal and other features 2:

• Wrist AND thumb sign = 3 points
• Pectus carinatum = 2 points
• Hindfoot deformity = 2 points
• Pneumothorax = 2 points
• Dural ectasia = 2 points
• Protrusio acetabuli = 2 points (relevant for Trendelenburg sign)
• Scoliosis or thoracolumbar kyphosis = 1 point
• Mitral valve prolapse = 1 point
• Myopia > 3 diopters = 1 point
• Skin striae = 1 point

Immediate Evaluation Required

Do not delay echocardiography even if the patient appears otherwise healthy. 2 Cardiovascular involvement is the most life-threatening aspect and the leading cause of mortality in Marfan syndrome 7, 6:

• Aortic root dilatation occurs in 81% of patients and develops in early childhood 6
• Both children and adults have similar high rates of aortic root dilatation, indicating these abnormalities develop early 6
• Mitral valve prolapse and aortic valve regurgitation show no significant difference in prevalence between children and adults 6

Comprehensive Workup

• Echocardiography to assess aortic root diameter and valve function 2, 6
• Ophthalmologic examination for ectopia lentis (requires specialized examination as it may be subtle) 2
• Skeletal assessment including evaluation for protrusio acetabuli, scoliosis, pectus deformities, and arachnodactyly 2
• Family history assessment: Personally examine parents and siblings for scoliosis, striae atrophicae, disproportionate stature, MVP, and aortic root dilation, as these are often clinically silent 2
• Genetic testing for FBN1 mutations 2, 4

Critical Differential Diagnosis

Loeys-Dietz Syndrome must be excluded as it carries a higher risk of aortic dissection even without significant dilation. 2 This syndrome can present with similar skeletal features but has distinct craniofacial features and more aggressive vascular disease.

Management If Marfan Syndrome Confirmed

β-blocker therapy is indicated for all patients with aortic root dilation or meeting diagnostic criteria for Marfan syndrome. 2

Surveillance protocol: 2

• Annual echocardiography for aortic root diameter <4.5 cm in adults AND growth rate <0.5 cm/year
• Echocardiography every 6 months when diameter >4.5 cm OR growth rate >0.5 cm/year
• Complete aortic imaging (MRA or CT) starting in young adulthood

Critical Pitfalls to Avoid

• Do not dismiss this as isolated familial tall stature or benign joint hypermobility without comprehensive cardiovascular evaluation 2
• Do not assume normal vision excludes Marfan syndrome—ectopia lentis requires specialized ophthalmologic examination 2
• Do not attribute all findings to Marfan syndrome—the precocious puberty requires separate endocrine investigation 2
• Recognize that cardiovascular abnormalities develop in early childhood, making early identification crucial for preventing life-threatening complications 6