Peripheral precocious puberty in girls with McCune-Albright syndrome: a case series

Faria, Aline Guimarães; Montenegro, Luciana R.; Jorge, Alexander Augusto Lima; Martin, Regina Matsunaga; Fragoso, Maria Candida Barisson Villares; Tinano, Flavia R.; Seraphim, Carlos E.; Canton, Ana Pinheiro Machado; Gomes, Larissa G.; Martos-Moreno, Gabriel A.; García, Irene Tarjuelo; Carcavilla, Atilano; Tirado-Capistros, Mireia; Souza-Pinto, Nadja Cristhina; Argente, Jesús; Latronico, Ana Claudia; Mendonca, Berenice Bilharinho; Brito, Vinicius Nahime

doi:10.20945/2359-4292-2024-0459

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original • Arch. Endocrinol. Metab. 69 (2) • 2025 • https://doi.org/10.20945/2359-4292-2024-0459 linkcopy

Peripheral precocious puberty in girls with McCune-Albright syndrome: a case series

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective: To describe the follow-up of girls with peripheral precocious puberty (PPP) due to McCune-Albright syndrome (MAS). Subjects and methods: Data from 18 females, including anthropometric and reproductive outcomes, were evaluated. Genetic analysis was performed on DNA from peripheral leukocytes via digital PCR. Results: Clinical manifestations of PPP were isolated thelarche, thelarche plus vaginal bleeding, or isolated vaginal bleeding in 44.5%, 33.3%, and 22.2%, respectively, at an early age (3.3 ± 1.6 years). At diagnosis, basal LH and FSH levels were suppressed in 100% and 72.2% of cases, respectively, and estradiol ranged from prepubertal to high levels. The mean bone age advancement was 2.3 ± 1.9 years. Treatment included medroxyprogesterone acetate, tamoxifen, aromatase inhibitors, and ketoconazole, individually or in combination for 5 ± 2.14 years, with partial or complete control of puberty. Secondary central precocious puberty was diagnosed in 57.1% (8/14) of the patients. Fibrous dysplasia was diagnosed in 11 patients and managed with bisphosphonates for those with bone pain. The mean adult height was 155.1 ± 8.7 cm (-1.17 SDS) in 10 patients. Menarche occurred at a mean age of 12.2 ± 1.04 years, 70% reported regular menstrual cycles and only one female desired pregnancy. Genetic diagnosis was established in 52.9% (9/17) of the patients. Conclusion: Medical treatment of PPP was effective in girls with MAS and led to preservation of adult height potential, and reproductive function was normal when patients reached adulthood

Keywords:
McCune-Albright syndrome; precocious puberty; aromatase inhibitors; tamoxifen; digital droplet PCR

Patient	First sign of precocious puberty	CA at first sign (yr)	CA at first medical examination (yr)	Height (SDS)	Tanner stage (B/PH)	BA-CA	OFD	Café-au-lait skin spots	Other endocrine hyperfunctions
1	VB	2.7	3.1	0.3	2/1	0.4	+	+	-
2	Thelarche + VB	3	6.5	1.54	4/1	5.5	+	+	-
3	VB	2	10	-1.0	3/4	-1.1	+	+	-
4	Thelarche	0.6	5	NA	3/2	-	+	+	Hyperthyroidism
5	Thelarche + VB	3	5.2	4.15	3/1	4.8	+	+	-
6	Thelarche + VB	3	4.8	-0.57	4/2	2.8	+	+	-
7	Thelarche	1.5	3.7	2.15	4/1	1.2	+	+	-
8	Thelarche	NA	9.1	0.0	2/2	1.9	-	+	-
9	VB	3.7	4.6	0.7	2/1	4.3	+	-	-
10	Thelarche	5.7	6.7	0.1	4/2	2	-	+	-
11	Thelarche	4	6.6	3.0	3/2	4	+	-	-
12	Thelarche	3	4.1	2.27	4/1	2.1	-	+	-
13	Thelarche + VB	4.9	6.2	1.36	3/1	4.8	-	+	-
14	Thelarche	4.9	6.9	0.0	2/1	1	-	+	-
15	Thelarche + VB	4	5	1.82	2/1	0.7	NA	+	-
16	Thelarche	4	4	0.55	2/1	3.5	+	-	-
17	Thelarche +VB	6.1	6.1	0.75	2/1	0.6	+	-	-
18	VB	0.2	0.5	-0.16	3/1	1.3	NA	+	-

Patient	LH (IU/L)		FSH (IU/L)		E₂ (pg/mL)	Assay	Ovarian cyst	Laterality	Largest diameter cyst	Bone lesion sites on scintigraphy
Patient	Basal	Peak*	Basal	Peak*	E₂ (pg/mL)	Assay	Ovarian cyst	Laterality	Largest diameter cyst	Bone lesion sites on scintigraphy
1	<0.15	-	<0.6	-	35.3	ECLIA	+	Unilateral	LO; 37 mm	Craniofacial
2	<0.6	-	<1	-	783.2	IFMA	+	Bilateral	NA	Craniofacial
3	<0.1	-	<1	-	46	IFMA	+	Unilateral	RO; 26 mm	Craniofacial, right lower limb
4	<0.6	-	<1	-	290	IFMA	+	Unilateral	NA	Craniofacial, bilateral lower and upper limbs
5	<0.15	1.5	0.19	7.6	222.5	IFMA	+	Unilateral	RO; 27 mm	Craniofacial, left upper and lower limbs
6	<0.6	<0.6	<1	< 1	133	IFMA	NA	NA	NA	Left upper and lower limbs, left ribs
7	<0.1	0.2	<1	<1	13	IFMA	-	-	-	Right hemi body
8	<0.6	-	4.1	NA	31	IFMA	+	Unilateral	RO; 45 cm³	Normal
9	<0.6	3.4	<1	8.4	14	IFMA	+	Unilateral	RO, 45 mm	Right upper and lower limbs
10	<0.6	-	<1	5.8	34	IFMA	+	Bilateral	NA	Normal
11	<0.6	<0.6	<1	<1	36	IFMA	-	-	-	Right lower limbs
12	<0.6	-	<1	NA	9.3	IFMA	+	Bilateral	10 mm (multiples)	Normal
13	<0.1	-	0.3	NA	134.1	ECLIA	-	-	-	Normal
14	<0.1	2.9	1.3	-	31.2	IFMA	+	Unilateral	NA	Normal
15	0.02	0.2	0.01	1.1	598	IFMA	+	Unilateral	LO; 44 mm	NA
16	<0.1	0.1	<0.3	1.2	<10	IFMA	+	Unilateral	35 mm	Craniofacial, left lower limb
17	0.14	NA	<0.1	NA	35	IFMA	+	Unilateral	RO; 22 cm³	Craniofacial, lower limbs
18	<0.1	NA	<0.1	NA	463	IFMA	+	Unilateral	24 mm	NA

Patient	ddPCR
Patient	Mutation detection	Fractional abundance
Classical Triad (n = 8)	4/8 (50%)
1	R201C	1.2%
2	-	-
3	-	-
4	R201H	5.1%
5	R201H	1.2%
6	-	-
7	R201H	0.26%
15	-	-
Two clinical features of MAS (n = 9)	5/9 (50%)
8	-	-
9	R201H	5.0%
10	NA	NA
11	R201H	0.66%
12	-	-
13	-	-
14	R201C	0.13%
16	R201H	1%
17	R201H	0.33%
18	-	-
Total (n = 17)	9/17 (52.9%)

Patient	Treatment	Secondary CPP	Adverse effects	VB during treatment	Duration of treatment (yr)	CA at the end of treatment (yr)	CA at menarche (yr)	Adult Height (cm/SDS)	Target Height (cm/SDS)
1	Letrozole	No	No	Yes	Under treatment	-	-	-	154.5/-1.2
2	TMX, Anastrozole, GnRHa	Yes	No	NA	4.2	11.3	12	152/-1.7	148.5/-2.2
3	MPA, TMX, GnRHa	Yes	No	NA	8	10	10.4	142/-3.3	157/-0.8
4	Left oophorectomy, Anastrozole, TMX, GnRHa	Yes	No	Yes	7	12	12.2	143.7/-3	NA
5	Anastrozole, MPA	NA	No	NA	NA	NA	NA	NA	163.5/0.21
6	TMX, Anastrozole, MPA	No	Hypertrichosis	Yes	7.1	NA	NA	152.6/-1.49	157.5/-0.78
7	Ketoconazole, TMX, GnRHa	Yes	Hypertrichosis	Yes	7.2	11	11.6	159/-0.5	NA
8	Right cystectomy Anastrozole or Letrozole	Yes	Laboratory hyperandrogenism	No	1.7	12	13.1	159/-0.5	156.7/-0.93
9	TMX, MPA	No	Hypertrichosis and uterine volume enlargement	Yes	6.2	11.4	13.6	149/-2.2	156.5/-0.95
10	TMX	NA	No	NA	Lost to follow-up	NA	NA	NA	169/1.13
11	MPA, Anastrozole, TMX, GnRHa	Yes	Edema	Yes	5.1	NA	12.1	160.8/-0.23	161/-0.2
12	TMX, GnRHa	Yes	No	No	5.1	11.3	12.4	167.5/0.8	159.5/-0.45
13	Ketoconazole	No	Adrenal insufficiency	No	Lost to follow-up	-	-	-	157/-0,8
14	MPA, TMX, GnRHa	Yes	No	No	4	11	NA	NA	NA
15	No treatment	NA	-	-	-	-	-	-	NA
16	Letrozole	NA	No	No	1.75	10	NA	-	NA
17	Right oophorectomy	No	No	No	-	-	13	165.5/0.4	169.5/0.9
18	Letrozole	No	No	No	Under treatment	-	-	-	NA

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[TFN1] VB: vaginal bleeding; BA: bone age; CA: chronological age; B: breast development; PH: pubic hair; OFD: osteofibrous dysplasia; NA: not available