Mitotane in the treatment of childhood adrenocortical carcinoma: a potent endocrine disruptor

Summary Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP. Learning points: Adrenocortical carcinoma is an important differential diagnosis for virilization in young children Mitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosis Mitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults. Patients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completed In our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.

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Homozygous SHBG Variant (rs6258) Linked to Gonadotropin-Independent Precocious Puberty in a Young Girl

Journal of the Endocrine Society ◽

10.1210/jendso/bvab125 ◽

2021 ◽

Author(s):

Victoria C Andriessen ◽

Marissa Lightbourne ◽

Chelsi Flippo ◽

Fabio R Faucz ◽

Angela Delaney ◽

...

Keyword(s):

Precocious Puberty ◽

Bone Age ◽

Serum Levels ◽

Young Girl ◽

Sex Hormone Binding Globulin ◽

Polycystic Ovaries ◽

Shbg Level ◽

History Of ◽

Laboratory Investigations ◽

Peripheral Precocious Puberty

Abstract Sex hormone-binding globulin (SHBG) in the blood is a major determinant of bioactivity for key sex steroids such as testosterone and estradiol. Low serum levels of SHBG have been associated with obesity, polycystic ovaries and metabolic syndrome, and other states associated with hyperandrogenemia. A 9-year, 6-month-old girl presented with a history of peripheral precocious puberty and aggressive behavior. The patient’s SHBG level was remarkably low for her age, at less than 5 nmol/L [reference range for a girl with a bone age of 10 years, 73 nmol/L (SEM= 10)](1). Upon genetic and protein analysis, the patient was found to have a homozygous missense potentially pathogenic variant in the SHBG gene (c.554 C>T, p.P185L); her parents were asymptomatic heterozygote carriers. Laboratory investigations supported the possible involvement of this genetic alteration in the patient’s phenotype. Various analyses of this variant support its pathogenicity, although the exact mechanism remains unclear. In conclusion, we present a genetic SHBG variant in the homozygote state that may have been associated with gonadotropin-independent precocious puberty in a young girl.

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Congenital Hypothyroidism with Precocious Puberty-A Case Report

TAJ Journal of Teachers Association ◽

10.3329/taj.v24i1.37450 ◽

2011 ◽

Vol 24 (1) ◽

pp. 48-50

Author(s):

M Sanaul Haque ◽

SN Hasnain ◽

MI Haque ◽

MA Hossain ◽

MI Bari

Keyword(s):

Case Report ◽

Congenital Hypothyroidism ◽

Precocious Puberty ◽

Vaginal Bleeding ◽

Rare Case ◽

Rare Condition ◽

Bone Age ◽

Pubic Hair ◽

Breast Development

Congenital hypothyroidism with precocious puberty is a rare condition. In this report a rare case of congenital hypothyroidism with precocious puberty is described. A 10 years old girl presented with feature of hypothyroidism together with breast development, vaginal bleeding, lack of pubic hair and delayed bone age. She also had multicystic ovaries. She was treated with L-thyroxine and improved TAJ 2011; 24(1): 48-50

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Isosexual precocious puberty with primary hypothyroidism: an interesting case report

International Journal of Reproduction Contraception Obstetrics and Gynecology ◽

10.18203/2320-1770.ijrcog20174078 ◽

2017 ◽

Vol 6 (9) ◽

pp. 4140

Author(s):

Kaliki Hymavathi ◽

Surekha Tadisetti ◽

Divya Pusarla ◽

Malini Devi Gottipati

Keyword(s):

Case Report ◽

Precocious Puberty ◽

Abdominal Mass ◽

Bone Age ◽

Interesting Case ◽

Primary Hypothyroidism ◽

Uterine Bleeding ◽

Breast Development ◽

Girl Child ◽

History Of

Isosexual precocious puberty in a girl child is defined as thelarche before 6 years in African–Americans and 7 years in Caucasians and menarche before the age of 9 years. In 1960, Van Wyk and Grumbach first described a syndrome characterised by breast development, uterine bleeding and multicystic ovaries in the presence of long standing primary hypothyroidism. We describe an interesting case of 8 year old girl presented with the complaint of abdominal mass with history of premature menarche and breast development. She is found to have gross hypothyroidism, hyperprolactinemia, prepubertal LH levels, multicystic ovaries and delayed bone age. Thyroid replacement amazingly settled her problems bringing her to normalcy.

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Central Precocious Puberty in a Three-Year-Old Girl

INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY ◽

10.24293/ijcpml.v27i3.1568 ◽

2021 ◽

Vol 27 (3) ◽

pp. 341

Author(s):

Suryani Jamal ◽

Liong Boy Kurniawan ◽

Suci Aprianti ◽

Ratna Dewi Artati ◽

Ruland DN Pakasi ◽

...

Keyword(s):

Physical Examination ◽

Precocious Puberty ◽

Tanner Stage ◽

Central Precocious Puberty ◽

Bone Age ◽

Breast Development ◽

Hypothalamic Hamartoma ◽

Secondary Sexual Characteristics ◽

Pelvic Ultrasonography ◽

Sexual Characteristics

Precocious puberty is defined as the onset of secondary sexual characteristics before 8 years of age in girls and 9 years in boys. Central Precocious Puberty (CPP) is caused by early activation of the hypothalamic-pituitary-gonadal axis. Laboratory test of LH, FSH, and Estradiol is recommended for monitoring suppressive effects from GnRHa therapy in the early three months and every six months. This study aimed to report a case of CPP in a 3-year and 3-month-old girl. A 3-year and 3-month-old girl went to the hospital with vaginal bleeding (menstruation), breast development, and pubic and axilla hair for 7-month-old. Physical examination found moderately ill with obesity, body weight 20 kg, height 98 cm. Tanner stage was A2M3P2, café au lait was found in the left forehead with size 7x3.5 cm. In March 2015 before GnRHa therapy, LH, FSH and Estradiol level increased with levels of 4.32 mlU/mL, 6.01 mlU/mL, and 67 pg/mL, and after 3 months of the treatment was 0.87 mlU/mL, 2.51 mlU/mL and <20 pg/mL. Pelvic ultrasonography showed suggestive precocious puberty, bone age 5-year and 9-month (Greulich and Pyle), CT-Scan of the brain showed hypothalamic tumor suspected hypothalamic hamartoma. This patient was treated with a GnRHa injection every 4 weeks. Leuprorelin is a synthetic non-peptide analogue of natural GnRH. The diagnosis was based on medical history, physical examination, laboratory, and radiological findings. The prognosis of the patient was good.

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Van Wyk-Grumbach syndrome and oligosyndactyly in a 6-year-old girl: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-020-02472-z ◽

2020 ◽

Vol 14 (1) ◽

Author(s):

Niranjalee Samanthika Egodawaththe ◽

Sumudu Nimali Seneviratne ◽

Suvini Gunasekara ◽

Sathika Manori Amarasekara ◽

Kumudu Weerasekara

Keyword(s):

Precocious Puberty ◽

Hormone Receptors ◽

Early Recognition ◽

Final Height ◽

Hormone Replacement ◽

Macrocytic Anemia ◽

Bone Age ◽

Breast Development ◽

Syndromic Diagnosis ◽

Stimulating Hormone

Abstract Background Van Wyk-Grumbach syndrome refers to the development of isosexual precocious pseudopuberty and multicystic enlarged ovaries in the presence of hypothyroidism and delayed bone age. It is a rare presentation of untreated hypothyroidism. The prepubertal response in Van Wyk-Grumbach syndrome is always isosexual and mediated by very high thyroid-stimulating hormone levels acting through the follicle-stimulating hormone receptors inducing a follicle-stimulating hormonal effect. Early recognition and thyroid hormone replacement can completely regress precocious puberty and ovarian enlargement, while improving the final height achievement. Oligosyndactly is a congenital bony abnormality and can manifest either as an isolated malformation or as a component of a syndromic diagnosis. However, development of hypothyroidism in children with this peculiar bony deformity has rarely been described in the medical literature, with the exception of Cenani-Lenz Syndactyly syndrome. Case presentation We report the case of a 6-year-old Sri Lankan girl who presented with a 2-day history of vaginal bleeding and exertional dyspnea. She had marked short stature (well below −3 standard deviations) with an upper segment to lower segment ratio of 1.47. This girl had isolated breast development of Tanner stage 2. She was diagnosed to have acquired hypothyroidism secondary to autoimmune thyroiditis and also had macrocytic anemia, pericardial effusion, gonadotropin-releasing hormone-independent precocious puberty with radiological evidence of pubertal changes in the uterus, and multicystic ovaries. Interestingly, she also had post-axial oligosyndactyly in both feet and right-sided clubfoot. The diagnosis of Van Wyk-Grumbach syndrome was made based on the clinical and laboratory features. Her symptoms were successfully managed with L-thyroxine therapy. Conclusions Acquired hypothyroidism is a relatively common endocrine disorder among children and early recognition is important to prevent serious complications like Van Wyk-Grumbach syndrome. Sexual precocity with delayed bone age and stunting should direct our minds toward this unique diagnosis. It is always necessary to identify the other associated anomalies in addition to the primary diagnosis since these features may direct to a syndromic diagnosis.

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Peripheral Precocious Puberty of Ovarian Origin in a Series of 18 Girls: Exome Study Finds Variants in Genes Responsible for Hypogonadotropic Hypogonadism

Frontiers in Pediatrics ◽

10.3389/fped.2021.641397 ◽

2021 ◽

Vol 9 ◽

Author(s):

Raja Brauner ◽

Joelle Bignon-Topalovic ◽

Anu Bashamboo ◽

Ken McElreavey

Keyword(s):

Exome Sequencing ◽

Precocious Puberty ◽

Vaginal Bleeding ◽

Hypogonadotropic Hypogonadism ◽

Plasma Concentrations ◽

Rare Condition ◽

Breast Development ◽

Functional Studies ◽

Pathogenic Variants ◽

Peripheral Precocious Puberty

Background: Peripheral precocious puberty of ovarian origin is a very rare condition compared to central form. It may be associated with an isolated ovarian cyst (OC). The causes of OC in otherwise healthy prepubertal girls is currently unknown.Methods: Exome sequencing was performed on a cohort of 18 unrelated girls presenting with prenatal and/or prepubertal OC at pelvic ultrasonography. The presenting symptom was prenatal OC in 5, breast development in 7 (with vaginal bleeding in 3) and isolated vaginal bleeding in 6. All had OC ≥ 10 mm. The girls had no other anomalies. Four patients had a familial history of ovarian anomalies and/or infertility.Results: In 9 girls (50%), candidate or known pathogenic variants were identified in genes associated with syndromic and non-syndromic forms of hypogonadotropic hypogonadism including PNPLA6, SEMA3A, TACR3, PROK2, KDM6A, KMT2D, OFD1, GNRH1, GNRHR, GLI3, INSR, CHD7, CDON, RNF216, PROKR2, GLI3, LEPR. Basal plasma concentrations of gonadotropins were undetectable and did not increase after gonadotropin-releasing hormone test in 3 of them whilst 5 had prepubertal values. The plasma estradiol concentrations were prepubertal in 6 girls, high (576 pmol/L) in one and not evaluated in 2 of them.Conclusions: In the first study reporting exome sequencing in prepubertal OC, half of the patients with OC carry either previously reported pathogenic variants or potentially pathogenic variants in genes known to be associated with isolated or syndromic forms of congenital hypogonadotropic hypogonadism. Functional studies and studies of other cohorts are recommended to establish the causality of these variants.

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Next-Generation Sequencing Identifies Different Genetic Defects in 2 Patients with Primary Adrenal Insufficiency and Gonadotropin-Independent Precocious Puberty

Hormone Research in Paediatrics ◽

10.1159/000492496 ◽

2018 ◽

Vol 90 (3) ◽

pp. 203-211 ◽

Cited By ~ 4

Author(s):

Chiara Guzzetti ◽

Carla Bizzarri ◽

Elisa Pisaneschi ◽

Mafalda Mucciolo ◽

Emanuele Bellacchio ◽

...

Keyword(s):

Next Generation Sequencing ◽

Adrenal Insufficiency ◽

Precocious Puberty ◽

Genetic Defects ◽

Next Generation ◽

Hydroxylase Deficiency ◽

Primary Adrenal Insufficiency ◽

Cyp21a2 Gene ◽

Peripheral Precocious Puberty ◽

Generation Sequencing

Background: The development of gonadotropin-independent (peripheral) precocious puberty in male children with primary adrenal insufficiency (PAI) is consistent with a defect in the genes encoding for the enzymes involved in steroid hormone biosynthesis. Methods: Two young boys presented with peripheral precocious puberty followed by PAI. In both patients, the analysis of CYP21A2 gene encoding 21-hydroxylase was normal. As a second step, a targeted next-generation sequencing (NGS) was performed in both patients using a customized panel of congenital endocrine disor ders. Results: Case 1 had a new homozygous variant in the CYP11B1 gene (c.1121+5G>A). Mutations of this gene cause congenital adrenal hyperplasia due to 11β-hydroxylase deficiency, an essential enzyme in the cortisol biosynthesis pathway. Case 2 showed a new hemizygous mutation in the NR0B1 gene (c.1091T>G), which encodes for DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita [AHC] and critical region on the X chromosome gene 1). NR0B1 mutations cause X-linked AHC and hypogonadotropic hypogonadism. Pathogenicity prediction software defined both mutations as probably damaging. Conclusions: Peripheral precocious puberty was the atypical presentation of 2 rare genetic diseases. The use of NGS made the characterization of these 2 cases with similar clinical phenotypes caused by 2 different genetic defects possible.

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Deep Learning-Based Ultrasound Imaging Diagnosis for Gonadotropin-Releasing Hormone Agonists Treatment of Central Precocious Puberty

Scientific Programming ◽

10.1155/2021/4512506 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Ruifang Qi ◽

Kun Yang ◽

Rongmin Li

Keyword(s):

Deep Learning ◽

Ultrasound Imaging ◽

Precocious Puberty ◽

Central Precocious Puberty ◽

Bone Age ◽

Gonadotropin Releasing Hormone ◽

Breast Development ◽

Imaging Diagnosis ◽

Ovarian Volume ◽

Uterine Volume

To explore the adoption of ultrasound imaging diagnosis based on deep learning of convolutional neural networks (CNNs) in the treatment of central precocious puberty (CPP) by gonadotropin-releasing hormone agonists (GnRHa), ultrasound imaging based on CNN was utilized to treat CPP. The bone age, uterine and ovarian volume, and breast development of incomplete precocious puberty (IPP) group and CPP group were observed and recorded. The peak values of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured. The uterine and ovarian volume before and after GnRHa treatment of CPP were compared. The results showed that the bone age (9.03 ± 1.07), uterine volume (2.37 ± 1.52), ovarian volume (2.36 ± 0.82 mL), and breast development of the CPP group were considerably higher in contrast to the IPP group and control group ( P < 0.05 ). The LH peak (11.97 ± 5.63) and FSH peak (12.89 ± 3.15) of the CPP group were substantially higher relative to the IPP group ( P < 0.05 ). The uterine volume (1.06 ± 0.42) and ovarian volume (1.12 ± 0.49) after treatment were inferior to those before treatment ( P < 0.05 ). In short, ultrasound images based on deep learning could diagnose precocious puberty, which could also provide a certain basis for GnRHa treatment of CPP, as well as an important basis for clinical diagnosis and treatment of precocious puberty.

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Precocious puberty in a 24 month old Nigerian girl: case report

Nigerian Journal of Paediatrics ◽

10.4314/njp.v47i4.10 ◽

2020 ◽

Vol 47 (4) ◽

pp. 358-360

Author(s):

I.O. Oluwayemi ◽

A.A. Afolabi ◽

E.O. Adeniji ◽

T.O. Ayeni

Keyword(s):

Precocious Puberty ◽

Elevated Serum ◽

Tanner Stage ◽

Bone Age ◽

Pubic Hair ◽

Breast Development ◽

Endocrine Disorders ◽

Essentially Normal ◽

History Of ◽

Age And Sex

Precocious puberty refers to the appearance of signs of puberty at an earlier age than is considered normal. It occurs ten times more commonly in girls than in boys. The overall incidence ranged from 1/5000 to 1/10,000 children. The cause is idiopathic in 90% of cases of female precocious puberty. We present BA a 24 month old female toddler who presented with one year history of progressive breast development and 6 month history of pubic hair growth. There was associated increasing weight, height and vaginal secretion. There was no similar occurrence in the family. Mother attained menarche at 14 years of age. Essential finding at presentation revealed a toddler who is heavy and tall for age with a weight of 17kg (>95th percentile for age and sex), height of 90.5cm (90th percentile for age and sex), Occipito-frontal circumference of 49cm (normal). Her sexual maturityrating was Tanner stage 3 for breasts and stage 2 for pubic hair. An assessment of precocious puberty was made. Her investigation result showed an advanced bone age of 5 years; elevated serum gonadotrophins in the pubertal range; and essentially normal cranial CT. Abdomino-pelvic USS showed an enlarged uterus for age, and a dominant right follicle with internal echo measuring 17.1mm X 15.2mm. Parents were counseled on the need for treatment to arrest the progression of precocious puberty but yet to respond because of financial constraint after 2 years of diagnosis. Female precocious puberty is ten times more common than male precocious puberty. The aetiology is idiopathic in 90% of cases and It is amenable to treatment. Integration of the investigation and treatment of childhood endocrine disorders into the National Health Insurance scheme will be a great panacea to the challenge of prompt management in developing countries. Keywords: Precocious, puberty, 24 months old, female, idiopathic, poverty, Nigeria

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An Approach to the Evaluation and Management of the Obese Child with Early Puberty

Journal of the Endocrine Society ◽

10.1210/jendso/bvab173 ◽

2021 ◽

Author(s):

Christine B Tenedero ◽

Krista Oei ◽

Mark R Palmert

Keyword(s):

Precocious Puberty ◽

Weight Status ◽

Adult Height ◽

Age At Onset ◽

False Negative ◽

Central Precocious Puberty ◽

Bone Age ◽

Breast Development ◽

Early Puberty ◽

Line Test

Abstract With the decline in age at onset of puberty and increasing prevalence of childhood obesity, early breast development in young, obese girls has become a more frequent occurrence. Here, we examine available literature to answer a series of questions regarding how obesity impacts the evaluation and management of precocious puberty. We focus on girls as the literature is more robust, but include boys where literature permits.Suggestions include: (1) Age cut-offs for evaluation of precocious puberty should not differ substantially from those used for non-obese children. Obese girls with confirmed thelarche should be evaluated for gonadotropin-dependent, central precocious puberty (CPP) to determine if further investigation or treatment is warranted. (2) Basal luteinizing hormone (LH) levels remain a recommended first-line test. However, if stimulation testing is utilized, there is a theoretical possibility that the lower peak LH responses seen in obesity could lead to a false negative result. (3) Advanced bone age (BA) is common among obese girls even without early puberty; hence its diagnostic utility is limited. (4) Obesity does not eliminate the need for MRI in girls with true CPP. Age and clinical features should determine who warrants neuroimaging. (5) BA can be used to predict adult height in obese girls with CPP to inform counselling around treatment. (6) Use of gonadotropin-releasing hormone analogues (GnRHa) leads to increased adult height in obese girls. (7) Obesity should not limit GnRHa use as these agents do not worsen weight status in obese girls with CPP.

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