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BACKGROUND: The data on Leydig cell hypoplasia (LCH) resulting from biallelic Luteinizing hormone/chorionic gonadotropin receptor (LHCGR) inactivating variants is limited to case series. METHODS: We aim to describe our patients and perform systematic review of the patients with LHCGR inactivating variants in the literature. Detailed phenotype and genotype data of 3 patients from our centre and 85 (46,XY: 67; 46,XX: 18) patients from 59 families with LHCGR-inactivating variants from literature were described. RESULTS: Three 46,XY patients(age 6-18 years) from our centre, with two reared as females, had two novel variants in LHCGR. Systematic review (including our patients) revealed 72 variants in 88 patients. 46,XY patients (n=70, 56 raised as females) presented with pubertal delay (n=41) or atypical genitalia(n=17). Sinnecker score ≥3 (suggesting antenatal hCG inaction) was seen in 80% (56/70), and hCG-stimulated testosterone was low (<1.1 ng/ml) in 77.4% (24/31), whereas puberty/postpubertal age, high LH (97.6%, 41/42) and low (<1.0 ng/ml) basal testosterone (94.9%, 37/39) was observed in most. FSH was elevated in 21/51 of these patients. Variants with <10% receptor function were exclusively seen in cohorts with Sinnecker 4/5 (10/15 vs. 0/5, p=0.033). 46,XX patients (n=18) presented with oligo/amenorrhea and/or anovulatory infertility and had polycystic ovaries (7/9) with median LH of 10 IU/L (1.2-38). CONCLUSION: In summary, this study comprehensively characterizes LHCGR variants, revealing genotype-phenotype correlations and informing clinical management of LCH. In 46,XY LCH patients, pubertal LH inaction is uniform with variable severity of antenatal hCG inaction. Few mutant LHCGR have differential action for LH and hCG.
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BACKGROUND: To elucidate the role of various imaging modalities for tumor localization in ectopic ACTH Cushing's syndrome (EAS). DESIGN AND METHOD: Systematic review of the literature published between January 2015-2024 was performed. Patients (290 EAS patients, 23.8% Occult) who underwent contrast enhanced CT (CECT) and at least one PET/CT-scan (68Ga-SSTR, FDG and/or F-DOPA) were included. RESULTS: The sensitivity for identifying EAS tumor was comparable across CECT (63.1%, n=290), SSTR-PET/CT (58.2%, n=187), and FDG-PET/CT (57.6%, n=191), but was poor for DOPA-PET/CT (30.8%, n=26). Sensitivity for detecting metastasis was also comparable across CECT (78%, n=73), SSTR-PET/CT (85.3%, n=41), and FDG-PET (73.7%, n=38). For localised lesions, sensitivity as per etiology and grade of NET were similar for three scans, with exception of Thymic NET and grade 1 NET where CECT was better than FDG PET/CT. In patients not localised on CECT, sensitivity of SSTR PET/CT was 33.3% (vs. 18.9% FDG-PET/CT) whereas for patients negative on CECT and FDG-PET, sensitivity of SSTR-PET/CT was 15%. In cases where CECT and SSTR-PET/CT failed to localize, the sensitivities of FDG-PET/CT and DOPA-PET/CT were only 5.7% (2/35) and 0% (0/9), respectively. SSTR-PET/CT has a distinct advantage with significantly lesser false positive (FP) lesions (2.6%, mostly in thyroid/or pancreas). In comparison, CECT and FDG-PET/CT had FP â¼11% (mostly in lung and/or mediastinum), most of which were negative on SSTR-PET/CT. CONCLUSIONS: As per the current evidence, SSTR-PET/CT can be considered as the scan of choice in EAS evaluation, and further research is needed as one-fourth of the lesions remain occult.
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OBJECTIVE: To describe the genotype-phenotype characteristics of patients with 21-hydroxylase deficiency from western India and ascertain the prevalence of various phenotypes of 21-hydroxylase deficiency. METHODS: Patients with 21-hydroxylase deficiency, diagnosed clinically and biochemically, were prospectively enrolled and classified into salt wasting (SW), simple virilizing (SV), and non-classic (NC) phenotypes and were subjected to genetic testing of CYP21A2 by targeted sequencing and multiplex ligation-dependent probe amplification (MLPA). RESULTS: Eighty (64; 46, XX) probands with 21-hydroxylase deficiency were analyzed. 41 had SW, 34 had SV, and 5 had NC phenotype. Disease-causing mutations were identified in 158/160 alleles. The common mutations were Deletions/Large Gene Conversions (Del/LGC, 25.6%), p.293-13A/C>G (22.5%), and p.Ile173Asn(18.75%). Exon 6 cluster mutations (Ile236Asn, Val237Glu, Met238Lys) and p.Val282Leu were absent. c.-113G>A+p.Pro31Leu (6.87%) and p.Phe405Ser (2.5%) were rare recurrent mutations with a possible founder effect. Two novel variants (Exon 1, p.Leu49Arg, Exon 8, p.Leu362Ter) were identified and were estimated to have low enzyme activity (<2%). CONCLUSION: Del/LGC were the most common mutations identified. The c.-113G>A+p.Pro31Leu and p.Phe405Ser were recurrent variants with possible founder effect. This study also reiterates the low prevalence of NC CAH in Indian cohorts.
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INTRODUCTION: Pituitary apoplexy (PA) in Cushing's disease (CD) is rare with data limited to case reports/series. METHODS: We retrospectively reviewed case records of PA in CD managed at our center from 1987 to 2023 and performed a systematic literature review. RESULTS: We identified 58 patients (44 females), including twelve from our center (12/315 CD, yielding a PA prevalence in CD of 3.8%) and forty six from systematic review. The median age at PA diagnosis was 35 years. The most common presentation was type A (79.3%) and symptom was headache (89.6%), with a median Pituitary Apoplexy Score (PAS) of 2. Median cortisol and ACTH levels were 24.9 µg/dl and 94.1 pg/ml, respectively. Apoplexy was the first manifestation of underlying CD in 55.2% of cases, with 31.1% (14/45) presenting with hypocortisolemia (serum cortisol ≤ 5.0 µg/dl), underscoring the importance of recognizing clinical signs/symptoms of hypercortisolism. The median largest tumor dimension was 1.7 cm (53/58 were macroadenomas). PA was managed surgically in 57.8% of cases, with the remainder conservatively managed. All five PA cases in CD with microadenoma achieved remission through conservative management, though two later relapsed. Among treatment-naïve CD patients with macroadenoma, PA-related neuro-deficit improvement was comparable between surgical and conservative groups. However, a greater proportion of surgically managed patients remained in remission longer (70% vs. 38.5%; p = 0.07), for an average of 31 vs. 10.5 months. CONCLUSION: PA in CD is more commonly associated with macroadenomas, may present with hypocortisolemia, and surgical treatment tends towards higher and longer-lasting remission rates.
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Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Apoplejia Hipofisaria , Humanos , Apoplejia Hipofisaria/epidemiología , Apoplejia Hipofisaria/patología , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Femenino , Estudios Retrospectivos , Adulto , Masculino , Persona de Mediana Edad , Hidrocortisona/sangre , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/metabolismoRESUMEN
Data on radiofrequency ablation (RFA) in tumor-induced osteomalacia (TIO) are restricted to case reports (~ 11 patients) and long-term follow-up data are further scarce. We describe our experience on managing TIO from a tertiary care center in India. Retrospective study of patients with localized TIO was performed and clinical, biochemical, treatment and follow-up details were retrieved. Normalization of serum phosphorus in absence of phosphate supplementation was defined as remission. Of 33 patients (23 males), 24 patients underwent surgery as first-line treatment, and early remission, delayed remission (> 1 month for phosphorus normalization) and persistence were observed 12, 3, and 9 patients at a median follow-up of 5 (4-9) years. The gender, age, tumor size, location of tumors and FGF23 levels were not statistically different in patients who were in remission after surgery versus those with persistent disease. Second/third line treatment included conventional medical treatment and/or repeat surgery (n = 3), radiotherapy (n = 3), peptide receptor radionuclide therapy (n = 1), RFA (n = 1). Two patients had transient worsening (weeks) of weakness post-surgery. 10 patients underwent RFA (first-line n = 9); at the last follow-up 5 (4-10) years, 7 are in remission. Two of three persistent disease patients had large tumors (5.6 and 3.6 cm). There were no RFA-related complications except local ulcer in one. Although persistent disease was present in a few patients in both arms, there was no recurrence in either RFA or surgical cohort. RFA provide durable response similar to surgery, persistence requires multi-modality treatment.
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Factor-23 de Crecimiento de Fibroblastos , Osteomalacia , Síndromes Paraneoplásicos , Ablación por Radiofrecuencia , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Estudios de Seguimiento , Ablación por Radiofrecuencia/métodos , Anciano , Resultado del Tratamiento , Neoplasias de Tejido Conjuntivo/cirugía , Adulto JovenRESUMEN
Burosumab, a monoclonal antibody directed against the fibroblast growth factor 23 (FGF23), has been approved for the treatment of X-linked hypophosphatemia (XLH). We conducted a systematic review to compare the efficacy and safety of burosumab versus conventional therapy (phosphorus and calcitriol) on XLH treatment. After a comprehensive literature search on MEDLINE/PubMed and Embase, we found nine studies for inclusion in the analysis. Risk of bias was assessed, and a random-effects model was used to determine the effect size. Clinical, biochemical, and radiological parameters of disease severity before and after treatment were analyzed and expressed in standardized mean difference (SMD). Burosumab resulted in normalization of phosphate homeostasis with an increase in renal tubular phosphate reabsorption and significant resolution of skeletal lesions (change in Thacher's total rickets severity score SMD: -1.46, 95% confidence interval [CI]: -1.76 to -1.17, p < 0.001, improvement in deformities, and decline in serum alkaline phosphatase levels [SMD: 130.68, 95% CI: 125.26-136.1, p < 0.001)]. Conventional therapy led to similar improvements in all these parameters but to a lower degree. In adults, burosumab normalized phosphorus levels (SMD: 1.23, 95% CI: 0.98-1.47, p < 0.001) with resultant clinical improvement. Burosumab treatment was well tolerated, with only mild treatment-related adverse effects. The present review indicates a potential role for burosumab in improving rickets, deformities, and growth in children with XLH. Given its superior efficacy and safety profile, burosumab could be an effective therapeutic option in children. We suggest further studies comparing burosumab versus conventional therapy in children and adults with XLH.
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Anticuerpos Monoclonales Humanizados , Raquitismo Hipofosfatémico Familiar , Factor-23 de Crecimiento de Fibroblastos , Humanos , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Resultado del Tratamiento , Calcitriol/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Fósforo/sangreRESUMEN
Glucocorticoid resistance syndrome is a rare disorder with no genetically proven cases reported from India; in addition, there are no descriptions available regarding its management during pregnancy. A 27-year-old woman, hypertensive since the age of 17 years, presented with hypokalemic paresis. She reported regular menses and acne. On investigation, she had elevated serum cortisol that remained unsuppressed after a low-dose dexamethasone suppression test. Genetic analysis revealed a novel, homozygous missense variant in exon 5 of the NR3C1 gene confirming glucocorticoid resistance syndrome. She was managed with oral dexamethasone followed by tapering of antihypertensive drugs. A year later, she conceived with assisted reproductive techniques when dexamethasone was replaced with prednisolone, necessitating the reintroduction of antihypertensive drugs to maintain normotension and potassium supplements to manage hypokalemia. She presented with acute abdomen at 36 weeks of gestation; evaluation revealed right adrenal hemorrhage, which was managed conservatively. Postpartum, the right adrenal lesion reduced in size and an underlying right adrenal myelolipoma was unveiled.
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Vitamin D is mainly produced in the skin (cholecalciferol) by sun exposure while a fraction of it is obtained from dietary sources (ergocalciferol). Vitamin D is further processed to 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D (calcitriol) in the liver and kidneys, respectively. Calcitriol is the active form which mediates the actions of vitamin D via vitamin D receptor (VDR) which is present ubiquitously. Defect at any level in this pathway leads to vitamin D deficient or resistant rickets. Nutritional vitamin D deficiency is the leading cause of rickets and osteomalacia worldwide and responds well to vitamin D supplementation. Inherited disorders of vitamin D metabolism (vitamin D-dependent rickets, VDDR) account for a small proportion of calcipenic rickets/osteomalacia. Defective 1α hydroxylation of vitamin D, 25 hydroxylation of vitamin D, and vitamin D receptor result in VDDR1A, VDDR1B and VDDR2A, respectively whereas defective binding of vitamin D to vitamin D response element due to overexpression of heterogeneous nuclear ribonucleoprotein and accelerated vitamin D metabolism cause VDDR2B and VDDR3, respectively. Impaired dietary calcium absorption and consequent calcium deficiency increases parathyroid hormone in these disorders resulting in phosphaturia and hypophosphatemia. Hypophosphatemia is a common feature of all these disorders, though not a sine-qua-non and leads to hypomineralisation of the bone and myopathy. Improvement in hypophosphatemia is one of the earliest markers of response to vitamin D supplementation in nutritional rickets/osteomalacia and the lack of such a response should prompt evaluation for inherited forms of rickets/osteomalacia.
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Raquitismo Hipofosfatémico Familiar , Osteomalacia , Raquitismo , Deficiencia de Vitamina D , Humanos , Calcitriol , Receptores de Calcitriol , Osteomalacia/tratamiento farmacológico , Osteomalacia/etiología , Osteomalacia/metabolismo , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/tratamiento farmacológico , Raquitismo/tratamiento farmacológico , Raquitismo/etiología , Vitamina D/uso terapéutico , Vitamina D/metabolismo , VitaminasRESUMEN
OBJECTIVE: Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. A systematic review of phenotype-genotype correlation and data on testicular histology in LCAH patients is unavailable. We aim to describe our experience and provide phenotype-genotype correlation. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective review of three genetically proven LCAH patients from our centre and per-patient data analysis from a systematic review of 292 probands. The phenotypic subgroups of 46,XY were Group A (typical female genitalia), Group B (atypical genitalia) and Group C (typical male genitalia). RESULTS: We report three new LCAH probands from India, all diagnosed post-infancy with preserved gonadal function and one novel variant. The systematic review reports 46,XY to 46,XX LCAH ratio of 1.1 (155:140). Patients with 46,XY LCAH in Group A were diagnosed in infancy (116/117) and had higher mineralocorticoid involvement than Group C (96.4% vs. 75%, p = 0.035), whereas Group C had preserved gonadal function. Hyperplastic adrenals are noted in ~60% of LCAH diagnosed with primary adrenal insufficiency in infancy. There was no report of gonadal germ cell cancer and rare reports of germ cell neoplasia in situ in adolescents, especially with intraabdominal gonads. Two-thirds of LCAH probands were East-Asian and 11/16 regional recurrent variants were from East Asia. There was minimal overlap between variants in Groups A (n = 55), B (n = 9) and C (n = 8). All nonsense and frameshift and most of the splice-site variants and deletion/insertions were present in Group A. CONCLUSIONS: We report three new cases of LCAH from India. We propose a phenotype-derived genotypic classification of reported STAR variants in 46,XY LCAH.
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Hiperplasia Suprarrenal Congénita , Trastorno del Desarrollo Sexual 46,XY , Adolescente , Humanos , Masculino , Femenino , Hiperplasia Suprarrenal Congénita/diagnóstico , Mutación/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fenotipo , GenotipoRESUMEN
INTRODUCTION: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. MATERIALS AND METHODS: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. RESULTS: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. CONCLUSION: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.
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Raquitismo Hipofosfatémico Familiar , Síndrome de Fanconi , Hipofosfatemia Familiar , Osteomalacia , Raquitismo Hipofosfatémico , Humanos , Osteomalacia/genética , Raquitismo Hipofosfatémico Familiar/genética , Hipofosfatemia Familiar/genética , Hipofosfatemia Familiar/metabolismo , Síndrome de Fanconi/genética , Síndrome de Fanconi/metabolismoRESUMEN
Context: Data on the overnight 1â mg-dexamethasone suppression test (ONDST) in renal dysfunction are limited. Objective: We aim to determine the normative range of ONDST cortisol across chronic kidney disease (CKD) stages and reasons for its alteration. Methods: Prospectively, 180 CKD (30 each in G2-G5/5D) patients and 30 healthy controls underwent ONDST 8 Am serum cortisol (chemiluminescent immunoassay [CLIA]). In an exploratory cohort, 45 (15 each: G3b/G4, G5/G5D, and healthy controls) individuals' blood biochemistry for basal (8 Am) cortisol and adrenocorticotropin (ACTH), post-ONDST 8 Am dexamethasone, ACTH, cortisol (CLIA and liquid chromatography-tandem mass spectrometry), and 4 Pm cortisol was collected. Results: Post-ONDST cortisol (µg/dL) correlated inversely (râ =â 0.47; P < .005) with estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2), with 95th percentile being 1.2 in controls, 3.0 in G2, 3.2 in G3a, 4.3 in G3b, 4.7 in G4, 5.7 in G5, and 7.1 in G5D. In the exploratory cohort, basal 8 Am cortisol and ACTH, and post-ONDST dexamethasone were similar among controls and CKD subgroups. ONDST ACTH (for evaluating the hypothalamo-pituitary-adrenal axis) was slightly higher in G5/5D vs controls (8.9 vs 6.1â pg/mL), while it was similar in G3b/G4 vs controls. Median 8 Am ONDST cortisol was similar on CLIA and LC-MS/MS in controls and higher on CLIA in G3b/4 (1.7 vs 1.1â µg/dL; Pâ =â .012) and G5/5D (2.4 vs 1.7â µg/dL; Pâ =â .002) than LC-MS/MS. Post-ONDST serum cortisol drop from 8 Am to 4 Pm was significant in controls (0.5-<0.2â µg/dL) and G3b/4 (1.7-1.2â µg/dL), but not in G5/5D (2.4-2.2â µg/dL). Conclusion: The normative data of ONDST serum cortisol with eGFR-based cutoffs are useful in evaluating Cushing syndrome in CKD. Prolonged cortisol half-life and immunoassay-related assay cross-reaction are likely contributors to higher ONDST cortisol.
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BACKGROUND: Aromatase deficiency is a rare disorder, with only a few cases reported in India. We describe a single-center experience in western India, with a systematic review of genetically proven 46,XX aromatase deficiency patients to evaluate hormonal parameters. METHODS: Retrospective review of case records, collating phenotypic and genotypic data and molecular modeling. Systematic review of 46,XX aromatase deficiency, analyzing data on gonadotropins, estrogen and androgens. RESULTS: In the seven patients from our center, presentation was frequent in childhood or adolescence (4/7: delayed puberty or hyperandrogenism), with maternal virilization (4/7), predominance of Prader III/IV (5/7), and initial rearing as females (6/7). Three patients had hypoplastic ovaries. One patient had spontaneous regular menses. We report three novel (p.Arg115Pro, p.Arg192Pro, and c.145+1_145+4delins) and two recurrent variants (p.Val370Met, and c.145+1_145+4delins) in western and northern India, respectively. On systematic review (n=43), gonadotropins were elevated (FSH>LH) across ages (except preterm infants), androgens were elevated in about one-third of cases during childhood and puberty, and estradiol was lower than in controls in mini-puberty and puberty. Spontaneous thelarche and streak ovaries were significantly more frequent in patients with non-truncating and truncating variants, respectively. CONCLUSION: We report uncommon presentations with possible founder variants, and highlight hormonal parameters across ages. Serum FSH levels were elevated except in preterms, and can be used as a diagnostic marker.
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Trastornos del Desarrollo Sexual 46, XX , Aromatasa/deficiencia , Ginecomastia , Recien Nacido Prematuro , Infertilidad Masculina , Errores Innatos del Metabolismo , Masculino , Lactante , Femenino , Adolescente , Humanos , Recién Nacido , Andrógenos , Hormona Folículo Estimulante , GonadotropinasRESUMEN
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of phosphate homeostasis. We describe a single-center experience of genetically proven HHRH families and perform systematic review phenotype-genotype correlation in reported biallelic probands and their monoallelic relatives. Detailed clinical, biochemical, radiological, and genetic data were retrieved from our center and a systematic review of Pub-Med and Embase databases for patients and relatives who were genetically proven. Total of nine subjects (probands:5) carrying biallelic SLC34A3 mutations (novel:2) from our center had a spectrum from rickets/osteomalacia to normal BMD, with hypophosphatemia and hypercalciuria in all. We describe the first case of genetically proven HHRH with enthesopathy. Elevated FGF23 in another patient with hypophosphatemia, iron deficiency anemia, and noncirrhotic periportal fibrosis led to initial misdiagnosis as tumoral osteomalacia. On systematic review of 58 probands (with biallelic SLC34A3 mutations; 35 males), early-onset HHRH and renal calcification were present in ~ 70% and late-onset HHRH in 10%. c.575C > T p.(Ser192Leu) variant occurred in 53% of probands without skeletal involvement. Among 110 relatives harboring monoallelic SLC34A3 mutation at median age 38 years, renal calcification, hypophosphatemia, high 1,25(OH)2D, and hypercalciuria were observed in ~30%, 22.3%, 40%, and 38.8%, respectively. Renal calcifications correlated with age but were similar across truncating and non-truncating variants. Although most relatives were asymptomatic for bone involvement, 6/12(50%) had low bone mineral density. We describe the first monocentric HHRH case series from India with varied phenotypes. In a systematic review, frequent renal calcifications and low BMD in relatives with monoallelic variants (HHRH trait) merit identification.
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Entesopatía , Raquitismo Hipofosfatémico Familiar , Hipofosfatemia , Enfermedades Renales Quísticas , Nefrocalcinosis , Osteomalacia , Masculino , Humanos , Adulto , Raquitismo Hipofosfatémico Familiar/complicaciones , Raquitismo Hipofosfatémico Familiar/diagnóstico , Raquitismo Hipofosfatémico Familiar/genética , Hipercalciuria/complicaciones , Hipercalciuria/genética , Osteomalacia/complicaciones , Osteomalacia/genéticaRESUMEN
INTRODUCTION: Cushing's disease (CD) due to macrocorticotropinoma (MC) in children and adolescents is a rare entity with limited information regarding its characteristics. The objective of the study is to describe the clinical, biochemical, imaging, management, outcome, and genetic characteristics of children and adolescents with CD due to MC and compare them with those of microcorticotropinoma (mc). METHODS: This retrospective study was conducted at a single tertiary care center. Thirty-two patients with CD and MC (maximum tumor dimension ≥10 mm on imaging) and 65 patients with mc (<10 mm on imaging) aged ≤20 years at presentation were enrolled. RESULTS: Nineteen girls and 13 boys with MC presented at a median (IQR) age of 14.5 (12.0-17.9) years. Patients with MC had higher body mass index-standard deviation score (BMI-SDS) (3.70 ± 2.60 vs. 2.59 ± 2.01, p = 0.04), more frequent neuro-ophthalmic symptoms (25% vs. 9% p = 0.04) and short stature (59% vs. 34%, p = 0.049) but less frequent livid striae (53% vs. 77%, p = 0.01), hypokalemia (12% vs. 36%, p = 0.04), and lower cortisol (nmol/L) to corticotropin (pmol/L) ratio (41.20 vs. 55.74, p = 0.04) than those with mc. The remission (59% vs. 64%, p = 1.0) and relapse (53% vs. 37%, p = 0.26) rates after first-line surgery and remission rate after radiotherapy (RT) were comparable between the two cohorts, whereas time to remission after RT (27 vs. 13 months, p = 0.05) was longer in the MC group. A patient with MC had a pathogenic germline variant in CDH23. CONCLUSION: In this large monocentric series of pediatric CD, frequent mass effect symptoms and short stature, higher BMI-SDS, less frequent livid striae, and hypokalemia with lower effective cortisol secretion characterize the MC cohort. The outcomes of surgery and RT were similar between the groups except for a longer time to remission after RT in the MC cohort. Germline variants are rare (4%) in pediatric MC.
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Hipopotasemia , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Masculino , Femenino , Adolescente , Humanos , Niño , Hidrocortisona , Estudios Retrospectivos , Resultado del Tratamiento , Hormona Adrenocorticotrópica , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/terapia , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patologíaRESUMEN
ABSTRACT Objective: Data regarding rare FPAs from India, a resource limited setting, are limited. We describe a case series of rare FPAs from a single center in western India. Materials and methods: This was a retrospective case record review of patients diagnosed between January 2010 and July 2022. The diagnosis was based on biochemical (inappropriately elevated serum FSH/LH) and pathologic (positive immunostaining for FSH/LH) features in patients with FGA, and elevated serum thyroid hormones and normal/elevated TSH in patients with TSHomas. Results: We identified 11 patients with a total of six FGAs (median age 43.5 years, five men, one FGA cosecreting TSH, median largest dimension 40 mm, range 33-60 mm) and six TSHomas (median age 34.5 years, four women, two TSHomas cosecreting GH, median largest dimension 42.5 mm, range 13-60 mm). Symptoms of sellar mass effects led to pituitary imaging in most patients with FGA. Patients with TSHomas had symptoms of excess hormone secretion (GH/TSH) or sellar mass effects. The TSHomas that cosecreted GH/FSH were larger than those secreting only TSH. Transsphenoidal resection was the most common first-line therapy but significant residual disease was frequent (3 out of 6 FGAs and 4 out of 5 TSHomas). Conclusion: This is the first and second case series of FGAs and TSHomas, respectively, from India. In this study, TSHomas presented at younger age, were larger and had low surgical cure rates.
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ABSTRACT Burosumab, a monoclonal antibody directed against the fibroblast growth factor 23 (FGF23), has been approved for the treatment of X-linked hypophosphatemia (XLH). We conducted a systematic review to compare the efficacy and safety of burosumab versus conventional therapy (phosphorus and calcitriol) on XLH treatment. After a comprehensive literature search on MEDLINE/PubMed and Embase, we found nine studies for inclusion in the analysis. Risk of bias was assessed, and a random-effects model was used to determine the effect size. Clinical, biochemical, and radiological parameters of disease severity before and after treatment were analyzed and expressed in standardized mean difference (SMD). Burosumab resulted in normalization of phosphate homeostasis with an increase in renal tubular phosphate reabsorption and significant resolution of skeletal lesions (change in Thacher's total rickets severity score SMD: −1.46, 95% confidence interval [CI]: −1.76 to −1.17, p < 0.001, improvement in deformities, and decline in serum alkaline phosphatase levels [SMD: 130.68, 95% CI: 125.26-136.1, p < 0.001)]. Conventional therapy led to similar improvements in all these parameters but to a lower degree. In adults, burosumab normalized phosphorus levels (SMD: 1.23, 95% CI: 0.98-1.47, p < 0.001) with resultant clinical improvement. Burosumab treatment was well tolerated, with only mild treatment-related adverse effects. The present review indicates a potential role for burosumab in improving rickets, deformities, and growth in children with XLH. Given its superior efficacy and safety profile, burosumab could be an effective therapeutic option in children. We suggest further studies comparing burosumab versus conventional therapy in children and adults with XLH.
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Objective: Data regarding rare FPAs from India, a resource limited setting, are limited. We describe a case series of rare FPAs from a single center in western India. Materials and methods: This was a retrospective case record review of patients diagnosed between January 2010 and July 2022. The diagnosis was based on biochemical(inappropriately elevated serum FSH/LH) and pathologic (positive immunostaining for FSH/LH) features in patients with FGA, and elevated serum thyroid hormones and normal/elevated TSH in patients with TSHomas. Results: We identified 11 patients with a total of six FGAs (median age 43.5 years, five men, one FGA cosecreting TSH, median largest dimension 40 mm, range 33-60 mm) and six TSHomas (median age 34.5 years, four women, two TSHomas cosecreting GH, median largest dimension 42.5 mm, range 13-60 mm). Symptoms of sellar mass effects led to pituitary imaging in most patients with FGA. Patients with TSHomas had symptoms of excess hormone secretion (GH/TSH) or sellar mass effects. The TSHomas that cosecreted GH/FSH were larger than those secreting only TSH. Transsphenoidal resection was the most common first-line therapy but significant residual disease was frequent (3 out of 6 FGAs and 4 out of 5 TSHomas). Conclusion: This is the first and second case series of FGAs and TSHomas, respectively, from India. In this study, TSHomas presented at younger age, were larger andhad low surgical cure rates.
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Adenoma , Neoplasias Hipofisarias , Masculino , Humanos , Femenino , Adulto , Persona de Mediana Edad , Neoplasias Hipofisarias/diagnóstico , Estudios Retrospectivos , Adenoma/diagnóstico , Tirotropina , Gonadotropinas , Hormona Folículo EstimulanteRESUMEN
PURPOSE: Giant prolactinomas (GP) are rare tumors accounting for 4.3% of prolactinomas, with paucity of literature from India. We aim to describe clinical, biochemical, radiological, and treatment outcomes in a large series of Asian-Indian patients with GP. METHODS: A single-center retrospective analysis of GPs (n=84), age-based (adults: 66 versus pediatric: 18) and gender-based (males: 64 versus females: 20) comparison was done. RESULTS: The mean age at presentation was 34.1±13years, and 64 (76.2%) were males. Males were younger at presentation (32.1±12.2 versus 40.1±13.8years, P: 0.01). The majority presented with mass-effect-related manifestations (visual disturbances: 91.6%, headache: 84.5%) and/or hypogonadism (98.7%). At baseline, largest tumor dimension was 5.3±1.0cm, and serum prolactin was 8343 (3865.5-12,306) ng/mL; most (94.6%) had gonadal axis involvement. Dopamine-agonist (DA) as first-line therapy (45/67, 67.2%) achieved normoprolactinemia (maximum cabergoline dose: 2.0±1.2mg/week) in 36/45 (80%) and tumor response (≥50% reduction) in 36/37 (97.3%) patients at the last follow-up (median duration: 33 [14.5-53.5]months). Notably, gonadal axis recovery was poor (6/30, 20%) despite normoprolactinemia post-DA monotherapy. At latest follow-up, secondary hypothyroidism (32.5% versus 82.6%, P: 0.001) and central hypocortisolism (5.6% versus 42.9%, P: 0.007) were less frequent in DA monotherapy (n=43) than in multimodal therapy group (n=23). The proportion of males (94.4% versus 71.2%, P: 0.04) was higher in the pediatric age group, with DA-induced (first-line) normoprolactinemia observed in 66.7% of them. CONCLUSION: GP has male predominance, DA as first-line therapy normalized prolactin in four-fifths of patients with better preservation of HPT and HPA axes in patients with DA monotherapy.
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Neoplasias Hipofisarias , Prolactinoma , Adulto , Femenino , Humanos , Masculino , Niño , Prolactinoma/tratamiento farmacológico , Prolactinoma/patología , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/epidemiología , Estudios Retrospectivos , Prolactina/uso terapéutico , Ergolinas/uso terapéutico , Agonistas de Dopamina/uso terapéuticoRESUMEN
OBJECTIVE: The data on clinical, biochemical, radiological characteristics, and outcomes in paediatric ectopic adrenocorticotropic hormone syndrome (EAS) are limited owing to rarity of the condition. We report three new cases and perform a systematic review of paediatric EAS. DESIGN AND METHOD: Case records of paediatric and adolescent EAS patient's ≤20 years presenting at our centre between 1997 and 2021 were retrospectively reviewed, and a systematic review of the literature published between January 1970 and December 2022 was performed. RESULTS: A total of 161 patients including 3 new patients from our centre were identified. Bronchial neuroendocrine tumours (NET) (28.5%), thymic NET (22.9%), primitive cell-derived tumours (18.6%), and gastro-entero-pancreatic-NET (13.7%) were the common causes. Primitive cell-derived tumours were the most common in the first decade (24/45, 53.4%) and were the largest (82 [60-100] mm), whereas bronchial NETs predominated during the second decade (42/116, 36.2%) and were the smallest (15 [10-25] mm). Computed tomography localized 92.9% (118/127) of paediatric EAS patients. Immediate postoperative remission was attained in 77.9% (88/113) patients, whereas 30.4% (24/79) relapsed over a median (IQR) period of 13 (8-36) months. Over a median (IQR) follow-up of 2 (0.6-4.6) years, 31.4% of patients died. The median survival was higher in bronchial NET than in other tumour groups. Distant metastasis and tumour size were independent negative predictors of survival. CONCLUSIONS: Aetiological profile of paediatric and adolescent EAS is distinct from that of adults. Bronchial NETs have the best long-term survival, whereas distant metastasis and tumour size predict poor survival.
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Síndrome de ACTH Ectópico , Síndrome de Cushing , Neoplasias Pulmonares , Adolescente , Adulto , Niño , Humanos , Síndrome de ACTH Ectópico/complicaciones , Hormona Adrenocorticotrópica , Síndrome de Cushing/etiología , Neoplasias Pulmonares/complicaciones , Estudios RetrospectivosRESUMEN
OBJECTIVE: To describe the characteristics of gonadotropin-dependent precocious puberty (GDPP) in Indian children. METHODS: Clinical profiles of GDPP (n=78, 61 females) and premature thelarche (n=12) from a single center in Western India were retrospectively studied. RESULTS: Pubertal onset was earlier in boys than girls (29 vs 75 months, respec-tively; P=0.008). The basal luteinizing hormone (LH) was ≥0.3 mIU/mL, except 18% of GDPP girls. At 60 minutes after GnRHa-stimulation, all patients (except one girl) had LH ≥5 mIU/mL. The GnRHa-stimulated LH/FSH ratio was ≥0.34 at 60 minutes in girls with GDPP unlike premature thelarche. Only one girl had an allergic reaction to long-acting GnRH agonist. Among GnRH agonist-treated girls (n=24), the predicted final adult height was -1.67±1.5 SDS, whereas the attained final height was -0.25±1.48 SDS. CONCLUSION: We establish the safety and efficacy of long acting GnRH agonist therapy in Indian children with GDPP. The 60-minute stimulated serum LH/FSH of ≥0.34 differentiated GDPP from premature thelarche.