A dermatological assessment of pediatric patients with tuberous sclerosis complex (TSC)<sup/>

Nunes, Beatriz Azevedo; Romano, Ana Karolina Ferreira Gonçalves; Morgan, Mariana Aparecida Pasa; Gonçalves, Alice Andrade; Cardozo, Laís Faria Masulk; Almeida, Luiz Gustavo Dufner de; Haddad, Luciana Amaral; Crippa, Ana Chrystina de Souza; Antoniuk, Sergio Antonio; Abagge, Kerstin Taniguchi

doi:10.1016/j.abd.2023.11.004

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Original Article • An. Bras. Dermatol. 99 (5) • Sep-Oct 2024 • https://doi.org/10.1016/j.abd.2023.11.004 copy

A dermatological assessment of pediatric patients with tuberous sclerosis complex (TSC)^☆ ☆ Study conducted at the Complexo Hospital de Clínicas Universidade Federal do Paraná, Curitiba, PR, Brazil.

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background

Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous syndrome with variable phenotypes. Recent updates of TSC diagnostic criteria reaffirmed the defined genetic diagnostic criterion as the finding of a pathogenic DNA alteration in either TSC1 or TSC2 genes. It also slightly modified definite clinical diagnostic criteria. TSC-associated skin lesions in infancy are important clinical signs to select individuals with possible TSC for a closer clinical follow-up and genetic testing.

Objective

To raise awareness of the updated TSC diagnosis criteria; to assess the frequency of skin lesions in TSC patients as well as the first dermatological presentation; and to associate the findings with either TSC1 or TSC2 mutations.

Methods

Observational cross-sectional study. Clinical and genetic data were retrospectively collected from 37 TSC patients from a Brazilian University Hospital. Patients with skin signs were examined and prospectively assessed for 12 months.

Results

The earliest cutaneous lesions were hypomelanotic macules, which together with angiofibromas were the most frequent dermatological lesions. The total pathogenic DNA alteration ratio between TSC2 and TSC1 genes was 8:1. The frequency of a TSC2 pathogenic variant was 10-fold greater in the presence of ungual fibromas.

Study limitations

Small sample and a limited number of patients with TSC1 pathogenic variants.

Conclusion

Clinicians should be knowledgeable about TSC updated diagnostic criteria. Patients need to be followed up by a multidisciplinary team and treated accordingly. Early detection of cutaneous lesions is important for TSC diagnosis. A significant association between TSC2 gene pathogenic alterations and ungual fibromas is described.

Keywords
Genetic diseases; Neurocutaneous syndromes; Tuberous sclerosis complex; Tuberous Sclerosis Complex 1 gene; Tuberous Sclerosis Complex 2 gene

Major criteria	Minor criteria
Hypomelanotic macules (≥ 3, at least 5-mm diameter)	‘Confetti’ skin lesions
Facial angiofibromas (≥ 3) or fibrous cephalic plaque	Dental enamel pits (≥ 3)
Ungual fibromas (≥ 2)	Intraoral fibromas (≥ 2)
Shagreen patch	Retinal achromic patch
Multiple retinal hamartomas	Multiple renal cysts
Multiple cortical tubers and/or radial migration lines	Non-renal hamartomas
Subependymal nodules (≥ 2)	Sclerotic bone lesions
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma
Lymphangioleiomyomatosis^a a Combination of these two major criteria without other features does not meet the criteria for a definite diagnosis.
Angiomyolipomas (≥ 2)^a a Combination of these two major criteria without other features does not meet the criteria for a definite diagnosis.

Age and skin lesion	Female (n = 14)	Male (n = 13)	p
	[Median (IIQ); n (%)]	[Median (IIQ); n (%)]
Median age at first skin sign onset (months)	2.0 (0‒19)	3.0 (0‒7)	0.92^a a Mann-Whitney test.
Median age at TSC diagnosis (months)	18.0 (12‒36)	24.0 (7‒60)	0.78
First cutaneous sign
Hypomelanotic leaf macula	12 (92.9%)	13 (92.3%)	1.00^b b Fisher’s exact test, n = 27.
Confetti-like lesion	0 (0.0%)	2 (15.4%)	0.22^b b Fisher’s exact test, n = 27.
Fibrous cephalic plaque	2 (14.3%)	1 (7.7%)	1.00^b b Fisher’s exact test, n = 27.
Intraoral fibrous plaque	0 (0.0%)	1 (7.7%)	0.48^b b Fisher’s exact test, n = 27.
Gene harboring pathogenic alteration
TSC1	4 (20.0%)	1 (5.9%)	0.34^b b Fisher’s exact test, n = 27.
TSC2	16 (80.0%)	16 (94.1%)	0.34^b b Fisher’s exact test, n = 27.

Age, diagnosis and number of cutaneous signs	TSC1 (n = 5)	TSC2 (n = 32)	p
	[Median (IIQ); n (%)]	[Median (IIQ); n (%)]
Age and skin lesion
Median age at first skin sign onset (months)	0.0 (0‒18)^a a n = 5.	3.5 (0‒19)^b b n = 22.	0.39^c c Mann-Whitney test.
Median age at TSC diagnosis (months)	30.0 (15‒57)^a a n = 5.	15.0 (8‒60)^b b n = 22.	0.80^c c Mann-Whitney test.
Number of observed cutaneous signs
Hypomelanotic leaf macula	4 (80.0%)	31 (96.9%)	0.25^d d Fisher’s exact test.
Angiofibromas	5 (100.0%)	32 (100.0%)	1.00^d d Fisher’s exact test.
Fibrous cephalic plaque	4 (80.0%)	26 (81.2%)	1.00^d d Fisher’s exact test.
Confetti-like lesion	3 (60.0%)	23 (71.9%)	0.62^d d Fisher’s exact test.
Shagreen patches	4 (80.0%)	18 (56.2%)	0.62^d d Fisher’s exact test.
Ungual fibromas	1 (20.0%)	21 (65.6%)	0.13^d d Fisher’s exact test.
Intraoral fibromas	1 (20.0%)	8 (25.0%)	1.00^d d Fisher’s exact test.

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E-mail: revista@sbd.org.br

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[1] ⁎ Corresponding author. E-mail: kerstinabagge@gmail.com (K.T. Abagge)

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A dermatological assessment of pediatric patients with tuberous sclerosis complex (TSC)☆ ☆ Study conducted at the Complexo Hospital de Clínicas Universidade Federal do Paraná, Curitiba, PR, Brazil.

Abstract

Background

Objective

Methods

Results

Study limitations

Conclusion

A dermatological assessment of pediatric patients with tuberous sclerosis complex (TSC)^☆ ☆ Study conducted at the Complexo Hospital de Clínicas Universidade Federal do Paraná, Curitiba, PR, Brazil.