Precocious Pseudopuberty Research Articles

Genotype-phenotype correlation and feminizing surgery in Danish children with congenital adrenal hyperplasia

Introduction: Congenital adrenal hyperplasia (CAH) is characterized by a broad spectrum of symptoms. This study aims to describe genotype-phenotype correlations, clinical manifestations at diagnosis, and the frequency of feminizing surgery in childhood. Methods: A nationwide retrospective cohort study of patients diagnosed with CAH, aged ≤18, between 1943 and 2018. CAH was identified in national registries and validated through medical record reviews and phenotypically classified as salt-wasting (SW), simple virilizing (SV), or non-classic (NC) CAH. In a sub-cohort (diagnosed between 1999 and 2018) clinical data and feminizing surgery data were investigated. CYP21A2 variants were grouped as Null, A, B, C, and D. Results: The cohort comprised 379 patients with CAH. Genotype-phenotype correlations were as follows: Null and SW (100%), A and SW (94%), B and SV (51%), and C and NC (75%). In the subcohort (n=159, females=99) the female-to-male ratios were: SW=1.5, SV=1.1, and NC=2.3. Symptoms of precocious pseudopuberty dominated at diagnosis (39%). Males presented with significantly advanced bone age by the time of diagnosis (p=0.0009). In 53% of females (n=53), virilization of the external genitalia was present at the time of diagnosis, and in 46% (n=46) this developed already prenatally. Of the prenatal virilized females 85% underwent early feminizing genitoplasty. Virilization was identified in both mild and severe genotypes. Conclusion: Milder genotypes do not accurately predict CAH phenotype or prenatally reject serious outcomes such as virilization. The frequency of early genitoplasty is high among females with prenatal virilization. The delayed diagnosis and non-diagnosis of especially males with mild CAH advocate for a more prominent role of genetic testing in the diagnostic and screening for CAH.

21-Hydroxylase Deficiency Detected in Neonatal Screening: High Probability of False Negativity in Late Onset Form.

Despite the high sensitivity of neonatal screening in detecting the classical form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, one of the unclear issues is identifying asymptomatic children with late onset forms. The aim of this nationwide study was to analyse the association between genotype and screened level of 17-hydroxyprogesterone in patients with the late onset form of 21-hydroxylase deficiency and to quantify false negativity. In the Czech Republic, 1,866,129 neonates were screened (2006-2022). Among this cohort, 159 patients were confirmed to suffer from 21-hydroxylase deficiency, employing the 17-hydroxyprogesterone birthweight/gestational age-adjusted cut-off limits, and followed by the genetic confirmation. The screening prevalence was 1:11,737. Another 57 patients who were false negative in neonatal screening were added to this cohort based on later diagnosis by clinical suspicion. To our knowledge, such a huge nationwide cohort of false negative patients has not been documented before. Overall, 57 patients escaped from neonatal screening in the monitored period. All false negative patients had milder forms. Only one patient had simple virilising form and 56 patients had the late onset form. The probability of false negativity in the late onset form was 76.7%. The difference in 17-hydroxyprogesterone screening values was statistically significant (p<0.001) between severe forms (median 478.8 nmol/L) and milder (36.2 nmol/L) forms. Interestingly, the higher proportion of females with milder forms was statistically significant compared with the general population. A negative neonatal screening result does not exclude milder forms of 21-hydroxylase deficiency during the differential diagnostic procedure of children with precocious pseudopuberty.

Pseudo-precocious puberty in children exposed to exogenous sex hormone: case report series

Pseudo-precocious puberty in children exposed to exogenous sex hormone: case report series

Pseudo-Precocious Puberty Due to Non-Classic Form of Congenital Adrenal Hyperplasia Caused by 11 B-Hydroxylase Deficiency (CYP11B1 Mutation): A Case Report

Pseudo-Precocious Puberty Due to Non-Classic Form of Congenital Adrenal Hyperplasia Caused by 11 B-Hydroxylase Deficiency (CYP11B1 Mutation): A Case Report

Clinical Management and Therapy of Precocious Puberty in the Sapienza University Pediatrics Hospital of Rome, Italy.

Puberty identifies the transition from childhood to adulthood. Precocious puberty is the onset of signs of pubertal development before age eight in girls and before age nine in boys, it has an incidence of 1/5000-1/10,000 with an F:M ratio ranging from 3:1 to 20:1. Precocious puberty can be divided into central, also known as gonadotropin-dependent precocious puberty or true precocious puberty, and peripheral, also recognized as gonadotropin-independent precocious puberty or precocious pseudopuberty. Thus, the main aim of this narrative report is to describe the standard clinical management and therapy of precocious puberty according to the experience and expertise of pediatricians and pediatric endocrinologists at Policlinico Umberto I, Sapienza University of Rome, Italy. In the suspicion of early sexual maturation, it is important to collect information regarding the age of onset, the speed of maturation of secondary sexual features, exposure to exogenous sex steroids and the presence of neurological symptoms. The objective examination, in addition to the evaluation of secondary sexual characteristics, must also include the evaluation of auxological parameters. Initial laboratory investigations should include serum gonadotropin levels (LH and FSH) and serum levels of the sex steroids. Brain MRI should be performed as indicated by the 2009 Consensus Statement in all boys regardless of chronological age and in all girls with onset of pubertal signs before 6 years of age. The gold standard in the treatment of central precocious puberty is represented by GnRH analogs, whereas, as far as peripheral forms are concerned, the triggering cause must be identified and treated. At the moment there are no reliable data establishing the criteria for discontinuation of GnRH analog therapy. However, numerous pieces of evidence suggest that the therapy should be suspended at the physiological age at which puberty occurs.

THU187 Genotype-Phenotype Correlation, Clinical Presentation And Feminizing Surgery In Children With Congenital Adrenal Hyperplasia Due To 21-Hydroxylase Deficiency: A Nationwide Multi-Center Study

Abstract Disclosure: M. Lind-Holst: None. A. Berglund: None. M. Duno: None. G. Hvistendahl: None. M. Fossum: None. A. Juul: None. N. Jørgensen: None. K.M. Main: None. C.H. Gravholt: None. D. Hansen: None. Background: Congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency (21OHD) is a common autosomal recessive disorder caused by pathogenic variants in CYP21A2. Genotype cannot always predict severity and clinical consequences, and genotype-phenotype is only well correlated in the most severe clinical cases of CAH. Furthermore, non-classical CAH suffers from non-diagnosis, especially in males. Objective: Describe the genotype-phenotype correlation in Danish children with 21OHD and identify the most frequent pathogenic CYP21A2 variants. We describe the clinical manifestations at time of diagnosis and present data on virilization and feminizing surgery of females, stratified by genotype group during 20 years. Method: A national population-based study of all Danish children diagnosed with 21OHD, combining health registries and medical record data. We identified pathogenic variants in CYP21A2 and genotype-phenotype correlation. Clinical presentation at diagnosis and feminizing surgery in females was stratified by genotype group: Null, A, B, C and D, reflecting the preserved 21-hydroxylase activity in increasing order. Results: Variants frequency of 494 unique alleles: Deletion (31.8%) followed by I2G, Q318X, I172N, V281L, P30L, Cluster-E6, R356W and insT by 25.9%, 9.1%, 8.6%, 8.7%, 6.5%, 1.4%, 1.4% and 0.6%, respectively. Genotype-phenotype correlations: Null: 98%, A: 94%, B: 50%, C: 76%. Overall, 62 of the 159 children (67%) had evidence of pseudo-precocious puberty at time of diagnosis which was the most frequent group of symptoms in genotype group B: 8.2%, C: 23.3% and D: 3.8%. Bone age advancement was significantly more advanced at the time of diagnosis in males compared to females (p=0.0009). The most frequently reported symptom at diagnosis in the genotype group null (n=20) and A (n=31) were: clitoral hypertrophy in females: 62.7%, failure to thrive: 29% and salt-wasting crisis: 22%. Clitoral hypertrophy was also present in genotype group B, C and D and feminizing surgery was performed in 85% of prenatally virilized females and overall in 40% of females at a median age of 0.9 years [IQR 0.5-1.6]. Conclusion: Genotype groups only predict phenotype with high certainty in the null and A genotype groups. In a national cohort evidence of virilization in females and feminizing surgery were observed in every genotype group. Delayed or non-diagnosis in children with SV and NC CAH was substantial, especially in males. We suggest that children with even mild hyperandrogenic symptoms and normal biochemical markers for 21OHD may benefit from genetic testing for CAH to establish a diagnosis. Presentation: Thursday, June 15, 2023

Unequal crossing over between CYP11B2 and CYP11B1 causes 11 β -hydroxylase deficiency in a consanguineous family

Cytochrome P450 (CYP) family CYP11B2/CYP11B1 chimeric genes have been shown to arise from unequal crossing over of the genes encoding aldosterone synthase (CYP11B2) and 11β-hydroxylase (CYP11B1) during meiosis. The activity deficiency or impaired activity of aldosterone synthase and 11β-hydroxylase resulting from these chimeric genes are important reasons for 11β-hydroxylase deficiency (11β-OHD). Here，two patients with pseudoprecocious puberty and hypokalemia hypertension and three carriers in a consanguineous marriage family were studied. A single CYP11B2/CYP11B1 chimera consisting of the promoter and exons 1 through 5 of CYP11B2, exons 8 and 9 of CYP11B1, and a breakpoint consisting of part of exon 6 of CYP11B2 and part of exon 6, intron 6, and exon 7 of CYP11B1 were detected in the patients and carriers. At the breakpoint of the chimera, a c 0.1086 G > C ( p.Leu.362 =) synonymous mutation in exon 6 of CYP11B2, a c 0.1157 C＞G(p. A386V) missense mutation in exon 7 of CYP11B1, and an intronic mutation in intron 6 were detected. The allele model of the CYP11B2/CYP11B1 chimera demonstrated homozygosity and heterozygosity in the patients and the carriers, respectively. Molecular docking and enzymatic activity analyses indicated that the CYP11B2/CYP11B1 chimeric protein interacted with the catalytic substrate of aldosterone synthase and had similar enzymatic activity to aldosterone synthase. Our study indicated that deletion of CYP11B1 and CYP11B2 abolished the enzymatic activity of 11 β-hydroxylase and aldosterone synthase; however, the compensation of the enzymatic activity of aldosterone synthase by the CYP11B2/CYP11B1 chimeric protein maintained normal aldosterone levels in vitro. All of the above findings explained the 11β-OHD phenotypes of the proband and patients in the family.

128 - Van Wyk-Grumbach syndrome in an 8-year-old male with pseudo precocious puberty and unilateral cryptorchidism: a rare case report

128 - Van Wyk-Grumbach syndrome in an 8-year-old male with pseudo precocious puberty and unilateral cryptorchidism: a rare case report

Precocious Pseudo-Puberty in a 7-Year-Old Girl Due to Malignant Mixed Ovarian Germ Cell Tumor.

Precocious Pseudo-Puberty in a 7-Year-Old Girl Due to Malignant Mixed Ovarian Germ Cell Tumor.

A 12-Year-Old Girl with Juvenile Granulosa Cell Tumor of the Ovary, Presenting with Adolescent Hyperprolactinemia, Galactorrhea, and Amenorrhea.

BACKGROUND Juvenile-type granulosa cell tumors (JGCTs) are a rare subtype of sex cord stromal tumor with a characteristic histology that is commonly found in the first 3 decades of life. It most commonly presents with symptoms of hyperestrogenism, which may present as precocious pseudopuberty or as menstruation-related symptoms, allowing for early detection of the tumor. CASE REPORT We present the case of a 12-year-old girl who presented to her primary care provider (PCP) with secondary amenorrhea with intermittent abdominal pain, who underwent an ultrasound for further evaluation, which revealed a large incidental pelvic mass. She was admitted to the Emergency Department (ED) and had findings of galactorrhea and hyperprolactinemia on examination. Imaging studies demonstrated a large ovarian mass measuring 15.0×9.0×18.8 cm that was resected, and subsequent pathology results showed JGCT stage 1A. CONCLUSIONS Prognosis of granulosa cell tumors (GCT) largely depends on its initial size, stage at diagnosis, residual tumors after surgery, and the subtype of GCT. If the patient is of reproductive age, fertility-sparing surgical options must be considered and patients must be regularly monitored for recurrence. JGCTs can present with minimal to no symptoms of precocious puberty in young girls but may present with amenorrhea, which may be considered normal for their developmental age. Although JGCTs are rare, they are important to include in differential diagnoses of younger female patients with abdominal pain, especially if accompanied by hormonal irregularities.

Central Precocious Puberty Following Treatment of Precocious Pseudo-Puberty Caused by Leydig Cell Tumor: A Pediatric Case and Literature Review

Central Precocious Puberty Following Treatment of Precocious Pseudo-Puberty Caused by Leydig Cell Tumor: A Pediatric Case and Literature Review

A male child with Van Wyk-Grumbach syndrome and hypertrophic cardiomyopathy: a rare case with a rare association

Children with severe long-standing hypothyroidism rarely present with Van Wyk–Grumbach syndrome with delayed bone age and pseudoprecocious puberty. Till date, very few such cases are reported in boys. Boys are characterized by testicular enlargement with minimal penile enlargement. The prepubertal response in this syndrome is always isosexual and is mediated by very high thyroid-stimulating hormone levels acting through the follicle-stimulating hormone receptors. Although, hypothyroidism-induced dilated cardiomyopathy is an uncommon phenomenon, here we present a case of Van Wyk–Grumbach syndrome in a prepubertal boy with hypertrophic cardiomyopathy&#x0D; BIRDEM Med J 2022; 12(3): 226-229

Intracranial germinoma presenting as pseudo precocious puberty in a child with Down syndrome

The Journal is the primary organ of Continuing Paediatric Medical Education in Sri Lanka. The journal also has a website. Free full text access is available for all readers.The Sri Lanka Journal of Child Health is now indexed in SciVerse Scopus (Source Record ID 19900193609), Index Medicus for South-East Asia Region (IMSEAR), CABI (Centre for Agriculture and Bioscience International Global Health Database), DOAJ and is available in Google, as well as Google Scholar.The policies of the journal are modelled on the Committee on Publication Ethics (COPE) Guidelines on Principles of Transparency and Best Practice in Scholarly Publishing. Sri Lanka Journal of Child Health is recognised by the International Committee of Medical Journal Editors (ICMJE) as a publication following the ICMJE Recommendations.

Ovarian steroid cell tumor causing isosexual pseudoprecocious puberty in a young girl: an instructive case and literature review

BackgroundSteroid cell tumors (SCTs) are very rare sex cord-stromal tumors and account only for less than 0.1% of ovarian neoplasms. SCTs might comprise diverse steroid-secreting cells; hence, the characteristic clinical features were affected by their propensity to secrete a variety of hormones rather than mass effect resulting in compression symptoms and signs. To date, ovarian SCTs have seldom been reported in children, particularly very young children; and pseudoprecocious puberty (PPP) as its unique principal manifestation should be reiterated.Case presentationWe reported a 1-year-8-month-old girl presenting with rapid bilateral breast and pubic hair development within a 2-month period. Undetectable levels of LH and FSH along with excessively high estradiol after stimulation with gonadotropin-releasing hormone (GnRH), as well as a heterogeneous mass inside left ovary shown in pelvic sonography indicate isosexual PPP. Her gonadal hormones returned remarkably to the prepubertal range the day after surgery, and histology of the ovary mass demonstrated SCTs containing abundant luteinized stromal cells.ConclusionThe case highlighted that SCTs causing isosexual PPP should be taken into consideration in any young children coexistent with rapidly progressive puberty given a remarkable secretion of sex hormones. This article also reviewed thoroughly relevant reported cases to enrich the clinical experience of SCTs in the pediatric group.

Precocious puberty: experience in the Pediatric Endocrinology Unit at the Children's Hospital in Rabat

Introductionla puberté précoce est définie par le développement des caractères sexuels avant l´âge de 8 ans chez la fille et de 9 ans chez le garçon. L´objectif de notre étude était de décrire le profil clinique, paraclinique et étiologique de la puberté précoce.Méthodesil s´agit d´une étude descriptive rétrospective s´étalant de 1999 à 2017 à l´unité d´endocrinologie pédiatrique à l´Hôpital d´Enfant de Rabat.Résultatsquatre-vingt-dix-neuf (99) enfants ont été inclus. L´âge moyen des filles était de 4,25 ± 2,6 ans, celui des garçons était de 3,6 ans ± 1,8. Nous avons noté une prédominance féminine dans 90% (90 filles). Les signes révélateurs chez la fille étaient dominés par le développement mammaire (77,77%). Chez le garçon, le motif de consultation le plus fréquent était la pilosité pubienne (70%). Sur le plan biologique, dans les pubertés précoces centrales, le taux moyen du pic de LH après stimulation par GnRH était élevé à 17 UI/L avec un rapport moyen pic LH/ pic FSH de 1,30. Les étiologies étaient comme suit: pubertés précoces dissociées (60,60%), pubertés précoces pathologiques (39,40%). Dans cette dernière, nous avons noté une prédominance des pseudo-pubertés précoces (58,98%). Pour la puberté précoce centrale, la forme idiopathique était l´étiologie la plus fréquente chez la fille (62,5%). Alors que chez tous les garçons, une lésion du système nerveux central était objectivée.Conclusionnotre étude confirme que la puberté précoce pathologique centrale est souvent liée à une lésion du système nerveux central chez le garçon justifiant ainsi la réalisation systématique d´une imagerie cérébrale.

Случай сочетания синдрома пустого турецкого седла и опухоли надпочечника с ложным преждевременным половым развитием у четырехлетнего мальчика

Описан случай сочетания синдрома пустого турецкого седла и опухоли надпочечника с ложным преждевременным половым развитием у четырехлетнего мальчика. При этом у пациента до удаления опухоли надпочечника отмечалось ложное преждевременное половое созревание, а после удаления опухоли диагностирован гипогонадотропный гипогонадизм и низкорослость на фоне синдрома пустого турецкого седла. Необходимо назначение терапии генно-инженерным гормоном роста (у пациента зоны роста открыты), а также курсы терапии хорионическим гонадотропином.

Precocious pseudo-puberty in a 2-year-old girl, presenting with bilateral ovarian enlargement and progressing to unilateral juvenile granulosa cell tumour

Ovarian causes of precocious pseudo-puberty (PPP) include McCune-Albright syndrome (MAS) and juvenile granulosa cell tumour (JGCT). We describe a case of PPP in which bilateral ovarian enlargement with multiple cysts progressed to unilateral JGCT. A girl aged 2.17 years presented with 3 months of breast development, and rapid growth. Examination showed tall stature, height + 2.6 standard deviations, Tanner stage B3P2A1. A single cafe au lait patch was noted. Bone age was advanced at 5 years. Pelvic ultrasound showed bilaterally enlarged ovaries (estimated volumes 76 ml on the left, 139 ml on the right), each containing multiple cysts. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) values before/after gonadotrophin administration were 0.43/0.18 and < 0.1/<0.1 mUI/ml, serum estradiol 130 pg/ml, (prepubertal range < 20). PPP of ovarian origin was diagnosed, and Tamoxifen 20 mg daily started. However, after only 7 weeks height velocity escalated and breast development increased to B3-4 with menorrhagia. Basal/stimulated LH and FSH were still suppressed at 0.13/0.25 and <0.1/<0.1 mUI/ml, serum estradiol 184 pg/ml. Repeat imaging now showed normal right ovary (volume 1.8 ml) and a large left-sided vascular solid/cystic ovarian tumour which was excised (weight 850g). Histology showed JGCT, FIGO stage IA. DNA from tumour tissue showed no mutation in GNAS, exon 3 of AKT1 (which contains a mutational hotspot) or FOXL2. The observation that bilateral ovarian activity progressed to unilateral development of JGCT in this patient is novel. This case highlights current uncertainties in the ontology of JGCT, and its possible relationship with MAS.

Hormone Secreting Juvenile Granulosa Cell Tumor of the Ovary in an Infant Presenting with Massive Ascites and Precocious Pseudopuberty

Juvenile granulosa cell tumors (JGCTs), account for 4–5% of GCTs, the rare sex cord stromal tumors. Presentation of JGCTs in infants is even rarer. We present case of a 3-month-old female infant with abdominal distension, feeding intolerance and fever of 10 days' duration. The child had gross abdominal distension causing visible respiratory distress. She also had signs of isosexual precocious puberty. Radiological evaluation was suggestive of left ovarian tumor. Left oophorectomy with preservation of the fallopian tube was done after hemodynamic stabilization. Histopathology evaluation of the tumor was suggestive of JGCT, which was confirmed on immunohistochemical evaluation. On 1 year follow-up, the child is stable, has achieved age-appropriate milestones and is tumor-free. Parents have been explained importance of regular follow-up to detect tumor recurrence. This is probably the youngest case of JGCT presenting with precocious puberty reported in literature so far.

Tumor de células de la granulosa juvenil de ovario. Presentación inusual. Reporte de un caso

Granulose cell tumors represent 2% of ovarian tumors. They are classified as adult type and juvenile type. The juvenile type is associated with precocious pseudopuberty, irregular menstruation or nonspecific symptoms such as abdominal pain and palpable mass. More than 95% are confined to the ovary. A case of a 31-year-old patient is described. The patient consulted for 6-month evolution of increased abdominal volume and weight loss. Right ovary tumor was diagnosed. Tumor excision by gynecological laparotomy with positive frozen cut biopsy and surgical staging were performed. Pathological anatomy reported stromal tumor, and sexual cords suggestive of malignant juvenile granulose cell tumor. Immunohistochemistry reported positive inhibin B. It was concluded as stage IIIA2. This is a rare neoplasm with variable behavior. Accurate diagnosis is based on histological and immunohistochemical studies. Key words: Granulosa, Cell tumor, Juvenile granulosa cell tumor, Ascites, Diagnosis.

Primary juvenile hypothyroidism concurrent with huge bilateral cystic ovaries: Case report and literature review

Primary hypothyroidism can lead to delayed growth and pseudoprecocious puberty in juvenile patients, which was known as Van Wyk–Grumbach's syndrome (VWGS). There have been very few clinical case reports of primary juvenile hypothyroidism presenting with concurrent huge bilateral cystic ovaries. Here, we report the case of a 14-year-old female patient suffering from primary hypothyroidism in combination with bilateral cystic ovaries. Remarkable improvement of symptoms was observed after one month of hormone replacement therapy and an unnecessary surgical treatment was avoided. A comprehensive literature review of VWGS is summarised here to illustrate the presentation, diagnosis, and treatment of VWGS in pediatric patients. The present study aims to improve the current clinical knowledge of VWGS.