Turning our attention to melanoma risk in Turner syndrome

By Warren R. Heymann, MD, FAAD
July 2, 2025
Vol. 7, No. 26

“…at the endocrine clinic and in private practice, I had seen a few young girls who had not matured, and they were short in stature and they had short necks with a low hair line and increased carrying angle at the elbow. And I became intrigued with them and I was wondering what in the world could do this to them.” In June 1938, Dr. Henry H. Turner (1892 – 1970) presented his findings at the annual meeting of the Association for the Study of Internal Secretions in a paper entitled “A syndrome of infantilism, congenital webbed neck, and cubitus valgus,” describing 7 patients (6 adolescents, 1 adult). The paper was subsequently published in Endocrinology. (1)

Turner syndrome (TS) is the most common sex chromosomal abnormality in females. It results from a deletion or the nonfunctioning of one X chromosome in females. About half of the population with TS have monosomy X (45, XO). The other 50% have a mosaic chromosomal component (45, X with mosaicism). The missing X chromosome is from the mother’s ovum or the father’s sperm. Anomalies in the X chromosome that can lead to a nonfunctioning X chromosome include a) Isochromosome Xq (two copies of the long arm of the chromosome that are connected head to head); b) Ring chromosome (where a part of the ends of short and long arms of the X chromosome is missing); and c) an Xp or Xq deletion. (2,3)

TS occurs in approximately 1 in 2,500 female live births. Mousavi et al. state, “TS has a wide range of clinical symptoms. The most common symptoms are short stature and primary gonadal deficiency. The patient may have somatic features such as high arched palate, low posterior hairline, and cervical web. Other clinical features include horseshoe kidney, coarctation of the aorta, diabetes, hypothyroidism, hypertension, hearing loss, osteoporosis, bone fracture, and gastrointestinal problems. Skeletal anomalies such as cubitus valgus, Madelung deformity [a deficiency of the volar-ulnar aspect of the distal radius], and short fourth and fifth metacarpal and metatarsal bones are also seen. The diagnosis of TS is based on suggestive clinical findings and karyotype analysis of peripheral blood, which reveals the numerical and/or structural abnormalities of the X chromosome.” (3)

In their excellent review of TS in dermatology, Lowenstein et al. noted that an increased number of benign nevi have been reported in TS. Other cutaneous manifestations include lymphedema and disorders associated with TS-associated autoimmunity (alopecia areata, vitiligo). (4) This commentary will focus on nevi and the risk of melanoma in TS patients.

Becker et al. reported the first case of cutaneous melanoma in TS (there was a prior report of a choroidal melanoma) in a 61-year-old woman (karyotype 45, XO). The authors then performed a prospective examination of nevi of 10 TS patients. An average of 115 nevi were seen, with the majority measuring 0.1 to 0.5 cm. Most were distributed on the back and extremities. Clinical atypia was uncommon. (5) In their review, Lowenstein et al. reported a prevalence of an increased number of nevi in TS between 25% to 70%. They found only 5 reports of melanoma in TS (the patient from reference 4, 2 cases of metastatic melanoma with an unknown primary, anorectal melanoma, and a case of ocular choroidal melanoma). They suggested that patients with TS, despite the increased number of benign nevi (a well-established risk factor for melanoma), are not at an increased risk of melanoma, and perhaps the disorder could even confer an unknown protection against carcinogenesis. (4)

Clabbers et al. reported a 42-year-old woman with TS with > 200 nevi, of which approximately 60 were atypical nevi, who developed 4 superficial spreading melanomas and one melanocytic tumor of uncertain malignant potential. Although her family history was positive for melanoma, screening for high-risk melanoma genes (CDKN2A, CDK4, BAP1, TERT, POT1, and others) was negative. (6)

Alvarez et al. performed a matched case-control study of 66,313 melanomas in women at least 65 years old compared to 265,252 controls using the Surveillance, Epidemiology and End Results (SEER)-Medicare melanoma data. The authors identified a diagnosis of TS in 19 (0.03%) of the melanoma cases and in 19 (0.01%) of the controls. The statistically significant odds ratio (OR) for melanoma in individuals with TS was 4.0. Within the melanoma cohort, there was no significant difference between the stages of melanoma at presentation in those with or without TS. (7)

The reason for the increased number of nevi in TS remains enigmatic. It is unlikely that the absence of at least a portion of the X chromosome is pathogenic, as an increased number of nevi also occurs in Noonan syndrome. (5) Perhaps there is a hormonal influence. Growth hormone (GH) therapy is frequently used to treat short stature in TS. Although GH has been associated with some nevocyte abnormalities (anisokaryosis, human melanoma black-45 expression), use of GH is not associated with an increased number of acquired melanocytic nevi in children treated for GH deficiency. Ali et al. examined 61 TS patients (older than 18 years of age) for acquired melanocytic nevi (AMN). Their analysis found no association between karyotype, history of blistering sunburn, history of skin cancer, use of tanning booth, use of estradiol, or Fitzpatrick skin type, and the number of AMN in individuals with TS. However, participants with prior or current use of GH (n = 44) had significantly more AMN with a median count of 98.5 compared to 62 in those with no GH exposure (n = 17) (rate ratio 1.65, P = .03). (8)

In conclusion, although much remains to be learned about the pathogenesis of melanocytic nevi in patients with TS, the latest data suggests that GH may be responsible for an increased number of nevi in some patients and that there is a melanoma risk in patients with the disorder. Patients with TS should undergo routine screening for melanoma and abide by standard sun avoidance protocols.

Point to Remember: Patients with Turner syndrome have an increased risk of melanoma, possibly related to the number of nevi. The use of human growth hormone may contribute to the appearance of a larger number of acquired melanocytic nevi. Patients with Turner syndrome should be routinely screened for melanoma and practice standard sun avoidance techniques.

Our expert’s viewpoint

Megan Rogge, MD, FAAD
Associate Professor
Clerkship Director
Department of Dermatology
University of Texas, Health Science Center at Houston
McGovern Medical School

Individuals with Turner syndrome (TS) have a myriad of potential dermatologic findings, but among the most prevalent remains an increased number of acquired melanocytic nevi (AMN). Dr. Turner himself noted this increase in the very first patient he described with the condition that would go on to be named TS in 1938. The etiology of this increase has fascinated and perplexed me for the past several years. Dr. Heymann does an excellent job of summarizing the potential theories here and highlighting why it matters — we recently found that adults over 65 with TS have a four-fold increase in melanoma compared to their age-matched counterparts. (7) There is an established increased risk of melanoma in individuals with greater than 50 nevi and in my own study of 61 adults with TS, we found a median AMN count of 91, which may suggest the reason for increased melanoma in the TS population. (8)

In further examining the theories for increased AMN, a cross-sectional study of 236 patients with TS found no significant difference between the prevalence of increased melanocytic nevi (>50) in the monosomy and non-monosomy karyotypes, suggesting that this is not solely due to a deletion of the X chromosome. (9) We know that GH therapy induces changes in nevocytes, established as increasing the size of existing nevi, but not previously established as influencing the number of nevi. Our nevi count study is the first in adults with TS showing that those with current or prior use of GH therapy have a statistically greater number of AMN than those without GH therapy. GH therapy likely does not fully account for the increased number of AMN. As mentioned previously, children with GH deficiency treated with GH did not have an increased number of AMN compared to a control group of children, while children with TS treated with GH therapy did. (10) Further study is needed to elucidate the cause of AMN in TS, but until we uncover this, all patients with TS should have an annual skin screening, preferably by a dermatologist, and practice sun-protective behaviors.

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References

1. Schaefer GB, Riley HD. A tribute to Henry H. Turner, MD (1892-1970): A Pioneer Endocrinologist. The Endocrinologist 2004; 14 (4): 179-184.

2. Shankar Kikkeri N, Nagalli S. Turner Syndrome. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554621/

3. Mousavi, S., Amiri, B., Beigi, S. et al. The value of a simple method to decrease diagnostic errors in Turner syndrome: a case report. J Med Case Reports 15, 79 (2021). https://doi.org/10.1186/s13256-021-02673-0

4. Lowenstein EJ, Kim KH, Glick SA. Turner’s syndrome in dermatology. J Am Acad Dermatol 1004; 50: 767-776.

5. Becker B, Jospe N, Goldsmith LA. Melanocytic nevi in Turner syndrome. Pediatr Dermatol. 1994 Jun;11(2):120-4. doi: 10.1111/j.1525-1470.1994.tb00564.x. PMID: 8041650.

6. Clabbers JMK, Van Doorn R, Kukutsch NA. Turner Syndrome, Atypical Naevi and Multiple Melanoma: Coincidence or Causality? Acta Derm Venereol. 2023 May 5;103:adv5586. doi: 10.2340/actadv.v103.5586. PMID: 37144513; PMCID: PMC10171088.

7. Alvarez GV, Liao KP, Wehner MR, Rogge MN. Melanoma risk in Turner Syndrome: a case-control study in SEER-Medicare. J Am Acad Dermatol. 2024 Oct 9:S0190-9622(24)02961-X. doi: 10.1016/j.jaad.2024.09.055. Epub ahead of print. PMID: 39393551.

8. Ali I, Moore T, Kashyap A, Starling C, Thomas J, Truong VTT, Prakash SK, Rogge MN. Increased acquired melanocytic nevi in Turner syndrome associated with use of growth hormone: An observational study. J Am Acad Dermatol. 2024 Oct;91(4):744-746. doi: 10.1016/j.jaad.2024.06.034. Epub 2024 Jun 19. PMID: 38906258.

9. Said JT, Pithadia DJ, Snyder E, Elsharkawi I, Lin A, Lilly E. Dermatologic findings in individuals with Turner syndrome: A cross-sectional study across the lifespan. J Am Acad Dermatol. 2022 Aug;87(2):476-479. doi: 10.1016/j.jaad.2021.10.023. Epub 2021 Oct 22. PMID: 34688825.

10. Wyatt D. Melanocytic nevi in children treated with growth hormone. Pediatrics. 1999 Oct;104(4 Pt 2):1045-50. PMID: 10506263.

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