A Girl With Noonan Syndrome 9 Presenting With Bilateral Lower Limbs Lymphedema

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A Girl With Noonan Syndrome 9 Presenting With Bilateral Lower Limbs Lymphedema

Noonan syndrome (NS), a genetic disorder affecting 1 in 1,000–2,500 people worldwide, is defined by growth delays, heart defects, and distinct facial features. But when a 9-year-old Chinese girl developed persistent leg and vulvar swelling alongside classic NS traits, doctors at Beijing Children’s Hospital uncovered a rare subtype: Noonan syndrome 9 (NS9) linked to a SOS2 gene mutation. Their 2019 report, published in the Chinese Medical Journal, highlights the need for genetic testing to guide care in complex NS cases.

The study was led by Yuan Ding and Chun-Xiu Gong of the Department of Endocrinology, Genetics, and Metabolism at Beijing Children’s Hospital (Capital Medical University), with contributions from Xu-Yun Hu, Yi-Ping Shen, and colleagues at the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region and Boston Children’s Hospital.

The Patient’s Story

The girl, born to non-consanguineous parents, had a history of atrial (ASD) and ventricular (VSD) septal defects—fixed with surgery at 1 year old. At 3 years old, she developed left leg swelling with redness, warmth, and blisters. Eight months later, the right leg swelled too, and the edema spread to her vulva by age 6. Her parents initially overlooked her short stature (she was smaller than peers) but sought help when the swelling worsened.

At 9, her height (115 cm) and weight (21 kg) were below the 3rd percentile for her age. Physical exams revealed classic NS features: whole-body hyperpigmentation, curly hair, a low posterior hairline, prominent forehead, widely spaced eyes (hypertelorism) with down-slanting lids, low-set rotated ears, bilateral ptosis (droopy eyelids), protruding eyes, thick lips, and a broad, webbed neck. Her chest was wide with spaced nipples (14.5 cm apart).

The leg swelling was non-pitting—worse below the knees—with coarse, dark skin and scattered blue subcutaneous spots. Her vulva was also swollen and pigmented, with no pubic hair. She had mild intellectual disability, struggling in school.

Diagnostic Journey

Tests ruled out chromosomal abnormalities (46,XX) and Y-chromosome material (negative SRY). Leg vein ultrasounds were normal, but lymphatic imaging showed primary lymphatic dysplasia: bilateral lymphedema and a missing left venous angle (a key structure for lymph flow). These results confirmed the swelling was not from veins but faulty lymph vessels.

Genetic Breakthrough: SOS2 Mutation Confirms NS9

To classify her NS subtype, doctors sent samples to the Guangxi Maternal and Child Health Hospital’s Genetic and Metabolic Lab. They found a heterozygous SOS2 gene mutation (c.800T>A, p.M267K)—a known pathogenic variant for NS9. This is one of the few NS9 cases reported in Asian populations.

SOS2 mutations are extremely rare, accounting for <1% of NS cases. Yamamoto et al. first linked SOS2 to NS9 in 2015, noting that mutations in the gene’s Dbl homology (DH) domain (like p.M267K) are pathogenic. This makes sense because SOS1—a SOS2 homologue—has similar DH domain mutations linked to more common NS subtypes. Both genes regulate the Ras-MAPK pathway, a cell signaling system that controls growth and development. Faulty signaling here explains both NS symptoms and lymphedema.

Lymphedema in NS: A Rare but Critical Sign

Lymphatic problems affect <20% of NS patients, often linked to in utero edema (which explains traits like webbed necks or low-set ears). Before this case, only one family—a mother and son reported by Miller in 1978—had chronic leg edema starting in childhood (the mother at 7, the son at 16). This girl’s case is the second recorded instance of early-onset bilateral lower limb and vulvar lymphedema in NS.

Treatment and Safety: Why No Growth Hormone?

The girl received symptomatic care: rest, elastic compression bandages, and rehabilitation therapy. Notably, doctors avoided recombinant human growth hormone (rhGH), a common treatment for NS-related short stature. While a 2016 study found rhGH safe for 15 prepubertal NS children, the team chose caution: SOS1 and SOS2 are homologous, and some Ras-MAPK pathway mutations increase tumor risk. For this girl, the potential risks outweighed the benefits.

Key Takeaways for Families and Doctors

This case underscores two critical points:

  1. Genetic testing is non-negotiable: Subtyping NS (e.g., NS9 vs. other forms) guides treatment—like avoiding GH in high-risk mutations.
  2. Lymphedema should be on the radar: Unexplained swelling (even in the vulva) in NS patients with classic features may signal primary lymphatic dysplasia.

Conclusion

For families and clinicians, this report highlights the diversity of NS presentations. A child with short stature, heart defects, and unusual swelling may not just have “NS”—they could have a rare subtype like NS9, where genetic answers drive safer, more effective care. As the authors note, this is a rare but important case for Asian populations, adding to the global understanding of Noonan syndrome and its complications.

References:

  1. Noonan JA. Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Am J Dis Child. 1968;116:373–380. doi.org/10.1001/archpedi.1968.02100020377005
  2. Romano AA, Allanson JE, Dahlgren J, et al. Noonan syndrome: clinical features, diagnosis and management guidelines. Pediatrics. 2010;126:746–759. doi.org/10.1542/peds.2009-3207
  3. Yamamoto GL, Aguena M, Gos M, et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet. 2015;52:413–421. doi.org/10.1136/jmedgenet-2015-103018
  4. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355–369. doi.org/10.1146/annurev-genom-091212-153523
  5. Miller M, Motulsky AC. Noonan syndrome in an adult family presenting with chronic lymphedema. Am J Med. 1978;65:379–383. doi.org/10.1016/0002-9343(78)90836-7
  6. Tartaglia M, Zampino G, Gelb BD. Noonan syndrome: clinical aspects and molecular pathogenesis. Mol Syndromol. 2010;1:2–26. doi.org/10.1159/000276766
  7. Cordeddu V, Yin JC, Gunnarsson C, et al. Activating mutations affecting the Dbl homology domain of SOS2 cause Noonan syndrome. Hum Mutat. 2015;36:1080–1087. doi.org/10.1002/humu.22834
  8. Jeong I, Kang E, Cho JH, et al. Long-term efficacy of recombinant human growth hormone therapy in short-statured patients with Noonan syndrome. Ann Pediatr Endocrinol Metab. 2016;21:26–30. doi.org/10.6065/apem.2016.21.1.26

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