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BACKGROUND: Immunofixation electrophoresis (IFE) is the standard method for confirming the presence of a monoclonal protein (M-protein) at multiple myeloma (MM) diagnosis. IFE is also essential at assessment of complete response (CR) and stringent CR during treatment. As the CR assessment is influenced by daratumumab and isatuximab, HYDRASHIFT assays were developed. METHODS: Samples from patients under treatment that included daratumumab or isatuximab were tested and monitored by IFE on the HYDRASYS system using HYDRASHIFT assays (HYDRASYS/HYDRASHIFT) and by IFE on the Epalyzer2 system (Epalyzer). RESULTS: The IFE using HYDRASYS/HYDRASHIFT avoided a false positive caused by drug-related IgG-κ and contributed to accurate assessment of CR. Furthermore, HYDRASYS/HYDRASHIFT detected small M-proteins at early relapse and detected free light chains (FLCs) in patients with renal impairment exhibiting high serum FLCs despite being often missed on Epalyzer. CONCLUSION: Sensitivity and specificity of M-protein detection vary greatly depending on the IFE system and reagents used.
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Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais , Mieloma Múltiplo , Proteínas do Mieloma , Humanos , Anticorpos Monoclonais/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Proteínas do Mieloma/análise , Feminino , Idoso , Masculino , Pessoa de Meia-Idade , Imunoeletroforese/métodos , Resultado do Tratamento , Imunoglobulina G/sangue , Cadeias kappa de Imunoglobulina/sangue , Indicadores e ReagentesRESUMO
PURPOSE OF REVIEW: 21-Hydroxylase deficiency (21-OHD), the most common form of congenital adrenal hyperplasia, is an autosomal recessive disorder caused by pathogenic variants in CYP21A2 . Although this disorder has been known for several decades, many challenges related to its monitoring and treatment remain to be addressed. The present review is written to describe an overview of biochemical monitoring of this entity, with particular focus on overnight fasting urine pregnanetriol. RECENT FINDINGS: We have conducted a decade-long research project to investigate methods of monitoring 21-OHD in children. Our latest studies on this topic have recently been published. One is a review of methods for monitoring 21-OHD. The other was to demonstrate that measuring the first morning PT level may be more practical and useful for biochemical monitoring of 21-OHD. The first morning pregnanetriol (PT), which was previously reported to reflect a long-term auxological data during the prepubertal period, correlated more significantly than the other timing PT in this study, with 17-OHP, before the morning medication. SUMMARY: In conclusion, although the optimal method of monitoring this disease is still uncertain, the use of overnight fasting urine pregnanetriol (P3) as a marker of 21-OHD is scientifically sound and may be clinically practical.
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Hiperplasia Suprarrenal Congênita , Jejum , Pregnanotriol , Humanos , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/urina , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Criança , Pregnanotriol/urina , Jejum/urina , Biomarcadores/urina , Biomarcadores/sangue , Esteroide 21-Hidroxilase/genética , Esteroide 21-Hidroxilase/urina , Monitoramento Biológico/métodosRESUMO
CONTEXT: Primary adrenal insufficiency (PAI) is a life-threatening condition characterized by the inability of the adrenal cortex to produce sufficient steroid hormones. E3 ubiquitin protein ligase zinc and ring finger 3 (ZNRF3) is a negative regulator of Wnt/ß-catenin signaling. R-spondin 1 (RSPO1) enhances Wnt/ß-catenin signaling via binding and removal of ZNRF3 from the cell surface. OBJECTIVE: This work aimed to explore a novel genetic form of PAI. METHODS: We analyzed 9 patients with childhood-onset PAI of biochemically and genetically unknown etiology using array comparative genomic hybridization. To examine the functionality of the identified single-exon deletions of ZNRF3 exon 2, we performed three-dimensional (3D) structure modeling and in vitro functional studies. RESULTS: We identified various-sized single-exon deletions encompassing ZNRF3 exon 2 in 3 patients who showed neonatal-onset adrenal hypoplasia with glucocorticoid and mineralocorticoid deficiencies. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed that the 3 distinct single-exon deletions were commonly transcribed into a 126-nucleotide deleted mRNA and translated into 42-amino acid deleted protein (ΔEx2-ZNRF3). Based on 3D structure modeling, we predicted that interaction between ZNRF3 and RSPO1 would be disturbed in ΔEx2-ZNRF3, suggesting loss of RSPO1-dependent activation of Wnt/ß-catenin signaling. Cell-based functional assays with the TCF-LEF reporter showed that RSPO1-dependent activation of Wnt/ß-catenin signaling was attenuated in cells expressing ΔEx2-ZNRF3 as compared with those expressing wild-type ZNRF3. CONCLUSION: We provided genetic evidence linking deletions encompassing ZNRF3 exon 2 and congenital adrenal hypoplasia, which might be related to constitutive inactivation of Wnt/ß-catenin signaling by ΔEx2-ZNRF3.
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Zinco , beta Catenina , Recém-Nascido , Humanos , Criança , beta Catenina/genética , beta Catenina/metabolismo , Hipoadrenocorticismo Familiar/genética , Hibridização Genômica Comparativa , Ubiquitina-Proteína Ligases/genética , Via de Sinalização Wnt/genética , Éxons/genéticaRESUMO
CONTEXT: Adrenal crisis (AC) is a life-threatening complication that occurs during follow-up of patients with adrenal insufficiency (AI). No prospective study has thoroughly investigated AC in children with primary and secondary AI. OBJECTIVE: This work aimed to determine the incidence and risk factors for AC in patients with pediatric-onset AI. METHODS: This multicenter, prospective cohort study conducted in Japan enrolled patients diagnosed with AI at age ≤15 years. The incidence of AC was calculated as events per person-year (PY), and risk factors for AC were assessed using Poisson regression multivariable analysis. RESULTS: The study population comprised 349 patients (164 male, 185 female) with a total follow-up of 961 PY. The median age at enrollment was 14.3 years (interquartile range [IQR] 8.5-21.2 years), and the median follow-up was 2.8 years (IQR 2.2-3.3 years). Of these patients, 213 (61%) had primary AI and 136 (39%) had secondary AI. Forty-one AC events occurred in 31 patients during the study period. The calculated incidence of AC was 4.27 per 100 PY (95% CI, 3.15-5.75). Poisson regression analysis identified younger age at enrollment (relative risk [RR] 0.93; 95% CI, 0.89-0.97) and increased number of infections (RR 1.17; 95% CI, 1.07-1.27) as significant risk factors. Female sex (RR 0.99; 95% CI, 0.53-1.86), primary AI (RR 0.65; 95% CI, 0.30-1.41), or equivalent dosage of hydrocortisone per square meter of body area (RR 1.02; 95% CI, 0.96-1.08) was not a significant risk factor. CONCLUSION: A substantial proportion of patients with pediatric-onset AI experience AC. Younger age and an increased number of infections are independent risk factors for developing AC in these patients.
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Insuficiência Adrenal , Humanos , Masculino , Feminino , Insuficiência Adrenal/epidemiologia , Insuficiência Adrenal/etiologia , Incidência , Criança , Fatores de Risco , Adolescente , Estudos Prospectivos , Japão/epidemiologia , Adulto Jovem , Pré-Escolar , Seguimentos , Idade de Início , HidrocortisonaRESUMO
Introduction: Although the treatment success of long-term growth hormone therapy (GHT) is dependent on maintaining patients' adherence to treatment, marked variations in adherence levels among children with GHT (eg, 7-71% nonadherence) have been reported. Barriers to or promoters of GHT adherence have been discussed and investigated, and digital health technologies, such as electronic GH injection devices, may have the potential to assess adherence to GHT more accurately. Thus, we conducted a multicenter, retrospective cohort study using GH injection log analysis of an electronic GH device, GROWJECTOR®L, to qualify adherence and explore the factors influencing adherence. Methods: This study enrolled 41 patients (median[range] age, 5.8[3.0 ~ 17.0] years) with short stature from nine Japanese medical institutions. The injection log data (12-48 weeks) were read by smartphones and collected into the data center through a cloud server. Results: Although cumulative adherence rates remained higher than 95% throughout the observation period, five (12.2%) patients had low adherence (<85%). Subsequently, subgroup and logistic regression analyses for exploring factors affecting adherence revealed that self-selection of GH device and irregular injection schedule (ie, frequent injections after midnight) significantly affected adherence rate (p=0.034 and 0.048, respectively). In addition, higher rates of irregular injections significantly affected low adherence (median[range], 11.26[0.79 ~ 30.50]% vs 0.26[0.00 ~ 33.33]%, p = 0.029). Discussion: Our study indicated that injection log analysis using an electronic GH device could detect irregular injection schedules due to a night owl or disturbance in lifetime rhythm affecting low adherence and had significant potential to encourage collaborative monitoring of adherence with healthcare providers and patients themselves/caregivers, along with growing autonomy and shared decision-making. Our study suggests the significance of narrative and personal approaches to adherence of patients with GHT and the usefulness of digital devices for such an approach and for removing various barriers to patient autonomy, leading to improvement and maintenance of adherence.
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OBJECTIVES: The role of serum fibroblast growth factor 23 (FGF23) level in early neonatal period on the diagnosis of X-linked hypophosphatemic rickets (XLH) remains unclear. CASE PRESENTATION: Two female patients from the first pedigree had an affected mother, and the other female from the second pedigree had an affected father. In all three cases, FGF23 levels were high in cord blood and peripheral blood at day 4-5. Additionally, the FGF23 levels considerably increased from birth to day 4-5. We identified a PHEX pathogenic variant and initiated treatment during infancy in each case. CONCLUSIONS: In neonates with a parent diagnosed as PHEX-associated XLH, FGF23 in cord blood and peripheral blood at day 4-5 may be useful markers for predicting the presence of XLH.
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Biomarcadores , Raquitismo Hipofosfatêmico Familiar , Fator de Crescimento de Fibroblastos 23 , Humanos , Feminino , Biomarcadores/análise , Biomarcadores/sangue , Sangue Fetal/química , Recém-Nascido , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Raquitismo Hipofosfatêmico Familiar/sangue , Raquitismo Hipofosfatêmico Familiar/genética , Fator de Crescimento de Fibroblastos 23/análise , Fator de Crescimento de Fibroblastos 23/sangueRESUMO
Congenital adrenal hyperplasia is a category of disorders characterized by impaired adrenocortical steroidogenesis. The most frequent disorder of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which is caused by pathogenic variants of CAY21A2 and is prevalent between 1 in 18,000 and 20,000 in Japan. The clinical guidelines for 21-hydroxylase deficiency in Japan have been revised twice since a diagnostic handbook in Japan was published in 1989. On behalf of the Japanese Society for Pediatric Endocrinology, the Japanese Society for Mass Screening, the Japanese Society for Urology, and the Japan Endocrine Society, the working committee updated the guidelines for the diagnosis and treatment of 21-hydroxylase deficiency published in 2014, based on recent evidence and knowledge related to this disorder. The recommendations in the updated guidelines can be applied in clinical practice considering the risks and benefits to each patient.
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To manage of 21-hydroxylase deficiency (21-OHD), transition medicine from pediatric to adult health care is an important process and requires individually optimized approaches. We sent cross-sectional questionnaire surveys on the current status of transition from pediatric to adult health care in 21-OHD patients to all councillors of the Japanese Society for Pediatric Endocrinology. Many pediatric departments (42.2%) experienced adult 21-OHD patients, and 115 patients (53 males, mean age of 26) in 46 institutions were identified. Whereas almost two-thirds of pediatric endocrinologists regarded the problems of counterparts and cooperation as hindrance of transition medicine, the major reason for continuing to be treated in pediatrics was the patient's own request. The prevalence of long-term complications including obesity, osteoporosis, infertility, menstrual disorder, gender dysphoria, and testicular adrenal rest tumor were 27.5%, 8.8%, 11.1%, 26.3%, 7.1%, 12.5%, respectively, which is comparable to those of other cohorts previously reported. However, several items, especially infertility and osteoporosis were not checked well enough in adult 21-OHD patients treated in pediatrics. Though 44 of 62 female patients had genital reconstructive surgery, more than half of them were not followed up by gynecologists or pediatric urologists. Quite a few adult 21-OHD patients had been followed up in pediatrics even after coming of age; however, surveillance by pediatric endocrinologists of gynecological, reproductive, and mental problems may be insufficient. Therefore, multidisciplinary approaches should be required in transition medicine for 21-OHD and prerequisite for graduation of pediatrics. Pediatric endocrinologists will need to play a leading role in the development of transition systems.
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Hiperplasia Suprarrenal Congênita , Endocrinologistas , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/epidemiologia , Hiperplasia Suprarrenal Congênita/terapia , Adulto , Criança , Estudos Transversais , Feminino , Humanos , Japão/epidemiologia , MasculinoAssuntos
Mutação com Ganho de Função , Estudos de Associação Genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fenótipo , Adolescente , Biomarcadores , Criança , Pré-Escolar , Estudos de Associação Genética/métodos , Humanos , Imunofenotipagem , Lactente , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Acromesomelic dysplasia, type Maroteaux (AMDM) is a congenital bone dysplasia characterized by disproportionate, acromesomelic shortening of the limbs and mild spondylar dysplasia. AMDM is caused by biallelic loss-of-function mutations in NPR2 encoding natriuretic peptide receptor-B. We report on a 25-yr-old Japanese woman with AMDM. Her height was 119.0 cm (-7.4 SD) and weight 35 kg (-2.3 SD). She had acromesomelic shortening of limbs and severe brachydactyly. Radiological examination showed that her metacarpals and phalanges were short and wide, and her vertebral bodies were mildly flattened. Molecular analysis revealed a novel homozygous NPR2 mutation (c.1163G>A, p.Arg388Gln). We performed in vitro functional studies using HA-tagged wild-type (WT) and Arg388Gln vectors (HA-WT-NPRB and HA-R388Q-NPRB). Cells expressing HA-R388Q-NPRB showed negligible cGMP responses to C-type natriuretic peptide (CNP) stimulation, indicating that the mutation led to severe loss-of-function. By immunofluorescence experiments under permeabilized conditions, HA-WT-NPRB was expressed on plasma membrane, while HA-R388Q-NPRB co-localized with an Endoplasmic Reticulum marker. Cells co-expressing R388Q and the WT exhibited lower responses under CNP treatment than cells co-expressing the WT and empty vectors. Thus, it was thought that R388Q caused a dominant-negative effect with a defect in cellular trafficking to the plasma membrane.
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Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis that causes various symptoms such as skeletal malformations, disorders of sex development, and adrenal insufficiency. The aim of this study was to elucidate the clinical characteristics, especially age at diagnosis and treatment, of PORD from the perinatal period to adulthood in Japan. The first questionnaire was sent to 183 council members of the Japanese Society for Pediatric Endocrinology on 1 September 2018. The response rate was 65%, and a total of 39 patients with PORD were examined at 20 hospitals. The second questionnaire was sent in November 2018 to the council members examining these 39 patients with PORD. The response rate was 77%, and we received clinical information on 30 of the 39 patients. The two novel clinical findings were the age at diagnosis and the treatment of Japanese patients with PORD. In many cases, PORD can be diagnosed at <3 months of age. Hydrocortisone as the primary treatment during infancy can be used daily or in stressful situations; however, because patients with PORD generally have mild to moderate adrenal insufficiency, some might be able to avoid hydrocortisone treatment. Patients with PORD should be carefully followed up, and treatment should be optimized as for patients with other types of adrenal insufficiency. Other characteristics in the present study were similar to those described in previous reports.
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Fenótipo de Síndrome de Antley-Bixler/epidemiologia , Fenótipo de Síndrome de Antley-Bixler/terapia , Adolescente , Adulto , Idade de Início , Fenótipo de Síndrome de Antley-Bixler/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Gravidez , Inquéritos e Questionários , Adulto JovemRESUMO
Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a hemizygous mutation of the ABCD1 gene. Patients with ALD show progressive central nervous system demyelination and primary adrenal insufficiency. In Japan, most reported ALD cases were childhood-onset, and only one case of an adult patient with Addison's disease form of ALD has ever been reported. Herein, we present a case of a 29-year-old man with Addison's disease form of ALD. The patient had anorexia, weight loss, and skin pigmentation from 18 years of age. At first visit, his weight had decreased by 12 kg from 57 kg when he was 15 years old. Endocrinological examination showed low serum cortisol (1.2 µg/dL) with high plasma ACTH (4,750 pg/mL), and abdominal computed tomography showed normal adrenal glands. Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1 mutation, p.Gly116Arg, was identified in hemizygous state. He had no significant neurological findings on physical examination and no white matter lesions on brain magnetic resonance imaging (MRI). He was diagnosed with ALD presenting as Addison's disease, and glucocorticoid replacement therapy was initiated. Four years after the diagnosis, he still did not show any neurological findings and any white matter lesions on brain MRI. Evaluating VLCFA levels for ALD diagnosis is important in young adult men with idiopathic primary adrenal insufficiency as well as in children. Early diagnosis enables more rational approaches including the early detection of neurological complications and might improve the prognosis of patients.
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Doença de Addison/diagnóstico , Adrenoleucodistrofia/diagnóstico , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Doença de Addison/complicações , Doença de Addison/tratamento farmacológico , Doença de Addison/genética , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/patologia , Adrenoleucodistrofia/complicações , Adrenoleucodistrofia/tratamento farmacológico , Adrenoleucodistrofia/genética , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Diagnóstico Precoce , Glucocorticoides/administração & dosagem , Terapia de Reposição Hormonal , Humanos , Hidrocortisona/administração & dosagem , MasculinoRESUMO
BACKGROUND: C-type natriuretic peptide (CNP, NPPC) and its receptor, natriuretic peptide receptor-B (NPR-B, NPR2), are critical for endochondral ossification. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth. This study was performed to identify the NPR2 mutations in Korean patients with idiopathic short stature (ISS). METHODS: One hundred and sixteen subjects with nonsyndromic ISS were enrolled in this study, and the NPPC and NPR2 were sequenced. In silico prediction and in vitro functional analysis, using a cell-based assay, were performed to confirm their protein derangement. RESULTS: Mean age at diagnosis of ISS was 8.0 years, and the height z-score was -2.65. Three pathogenic variants (R921Q, R495C, and Y598N) and one benign variant (R787W) of the NPR2 were identified, while no novel sequence variant of the NPPC was found in all subjects. Two novel pathogenic mutants (R495C and Y598N) were predicted as highly pathogenic by several computational methods. In vitro study involving stimulation with CNP, R495C-, and Y598N-transfected cells showed decreased cGMP production compared to wild type-transfected cells. CONCLUSION: Heterozygous NPR2 mutations were found in 2.6% of ISS Korean subjects. This prevalence and the dominant-negative effect of mutant NPR-B on growth signals imply that it is one of genetic causes of ISS.
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Nanismo Hipofisário/genética , Mutação de Sentido Incorreto , Receptores do Fator Natriurético Atrial/genética , Animais , Células COS , Criança , Chlorocebus aethiops , Nanismo Hipofisário/patologia , Feminino , Humanos , Masculino , Receptores do Fator Natriurético Atrial/metabolismoRESUMO
Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR and characterized by a defect in steroidogenesis and lipid droplet accumulation in steroidogenic cells. Patients with 46,XY and classic LCAH will typically present with female-type external genitalia. However, those with nonclassic LCAH will have masculinized external genitalia. The rarity of the nonclassic form has precluded the clarification of the long-term outcomes of testicular function in nonclassic LCAH. We report the cases of three adult males with nonclassic LCAH in whom primary adrenal insufficiency had been diagnosed at 5 days, 4 years, and 5 years of age. All exhibited complete male external genitalia and had completed pubertal development without androgen replacement. The endocrinological data showed preserved gonadal function in patients 1 and 2 and hypergonadotropic hypogonadism in patient 3. Semen analyses showed normozoospermia in patient 1 and mild oligozoospermia in patient 2. Electron microscopic analysis of a testicular biopsy specimen from patient 2 at 13 years of age revealed prominent lipid accumulation in the cytosol of Leydig cells. Patients 1 and 2 shared the same compound heterozygous mutations in STAR (p.Glu258* and p.Arg272Cys). Patient 3 possessed a heterozygous dominant-negative mutation in STAR (p.Gly22_Leu59del). A functional assay of a variant STAR-Arg272Cys determined the residual activity as 35% of the wild-type STAR. The results from the present case series and a review of four previously reported adult cases indicate that testosterone synthesis can be preserved in most males with nonclassic LCAH to complete pubertal development and induce germ cell maturation despite lipid accumulation in the Leydig cells.
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Steroid 5α-reductase type 2 deficiency (5αRD2) is a congenital disorder of sex development caused by impairment of conversion from testosterone (T) to 5α-dihydrotestosterone (DHT). DHT deficiency leads to various degrees of undervirilized external genitalia including micropenis, primarily correlated with mutations of the SRD5A2 gene that encodes 5α-reductase type 2. Four Japanese boys with isolated micropenis were diagnosed as 5αRD2 by elevated ratios of serum T/DHT, and decreased ratios of urinary 5α/5ß-reduced steroid metabolites. Genetic analyses for SRD5A2 identified that the four patients shared a hypomorphic mutation R227Q that has a residual activity related to the mild-form of 5αRD2. For prepubertal micropenis, DHT was transdermally applied to the four patients at the ages of 4-11 year, increasing a median of stretched penile lengths (SPLs) from 2.6 cm (-2.5 SD) to 4.4 cm (-0.2 SD). Nevertheless, the post-pubertal penile growth was apparently retarded, despite normal levels of T secreted from well-developed testes. The second course of DHT treatment underwent at ages of 12-18 year, but unable to normalize SPLs at a range of 6.0 to 7.0 cm (-3.4 to -2.4 SD). The prostate volumes of two patients were variable at 8.1 and 21 cm3, and a sperm cell count of one patient was normal as young adult. DHT treatment contributes to development of the penis and prostate, which are favorable for the potential fertility of 5αRD2 adults. Meanwhile, the retarded penile growth and a risk of prostate overgrowth may complicate the post-pubertal management with DHT for 5αRD2 males.
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3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Di-Hidrotestosterona/administração & dosagem , Transtorno 46,XY do Desenvolvimento Sexual/tratamento farmacológico , Doenças dos Genitais Masculinos/tratamento farmacológico , Hipospadia/tratamento farmacológico , Pênis/anormalidades , Pênis/efeitos dos fármacos , Puberdade/efeitos dos fármacos , Erros Inatos do Metabolismo de Esteroides/tratamento farmacológico , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Criança , Pré-Escolar , Transtorno 46,XY do Desenvolvimento Sexual/sangue , Transtorno 46,XY do Desenvolvimento Sexual/genética , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Esquema de Medicação , Doenças dos Genitais Masculinos/sangue , Doenças dos Genitais Masculinos/genética , Humanos , Hipospadia/sangue , Hipospadia/genética , Hipospadia/patologia , Estudos Longitudinais , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Mutação , Pênis/crescimento & desenvolvimento , Pênis/patologia , Puberdade/fisiologia , Maturidade Sexual/efeitos dos fármacos , Erros Inatos do Metabolismo de Esteroides/sangue , Erros Inatos do Metabolismo de Esteroides/genética , Erros Inatos do Metabolismo de Esteroides/patologia , Testosterona/sangue , Fatores de Tempo , Resultado do TratamentoRESUMO
CONTEXT: Lipoid congenital adrenal hyperplasia (LCAH) is characterized by a disorder of steroidogenesis in both adrenal glands and gonads. 46,XX patients with classic LCAH usually have thelarche and menarche but show anovulatory menstruations and subsequent premature menopause. Only three patients with classic LCAH have been reported to successfully achieve delivery with the aid of assisted reproductive therapies for conception and progesterone replacement therapy during early pregnancy. In contrast, pubertal development and pregnancy outcomes in patients with nonclassic LCAH have not been fully elucidated. CASE DESCRIPTION: We report four Japanese women who had a diagnosis of primary adrenal insufficiency during infancy or childhood and carried compound heterozygous STAR mutations (p.Gln258* and p.Arg188His, p.Gln258* and p.Met225Thr, and p.Gln258* and p.Arg272Cys). In all four patients, thelarche and menarche spontaneously occurred from 10 to 11 years of age and from 12 to 14 years of age, respectively. Subsequently, their menstruation cycles were regular at almost 1-month intervals. Patient 1 conceived naturally twice, and patient 2 conceived with the use of clomiphene citrate for ovulation induction. These two patients maintained the pregnancies without progesterone replacement therapy and successfully delivered children. CONCLUSION: Patients with nonclassic LCAH maintain ovarian function, which enables normal pubertal development and a successful pregnancy outcome without progesterone replacement therapy.
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Transtornos 46, XX do Desenvolvimento Sexual/fisiopatologia , Hiperplasia Suprarrenal Congênita/fisiopatologia , Transtorno 46,XY do Desenvolvimento Sexual/fisiopatologia , Resultado da Gravidez , Puberdade/fisiologia , Transtornos 46, XX do Desenvolvimento Sexual/complicações , Transtornos 46, XX do Desenvolvimento Sexual/tratamento farmacológico , Adolescente , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Adulto , Transtorno 46,XY do Desenvolvimento Sexual/complicações , Transtorno 46,XY do Desenvolvimento Sexual/tratamento farmacológico , Feminino , Terapia de Reposição Hormonal , Humanos , Gravidez , Prognóstico , Adulto JovemRESUMO
BACKGROUND: The risk factors for rapid growth and early metastasis of papillary thyroid carcinoma (PTC) and the role of coexisting Graves' disease in the clinical course of PTC remain uncertain in children. CASE DESCRIPTION: We report on a Japanese girl, whose PTC rapidly grew and metastasized within 4 years. Graves' disease was diagnosed by the presence of serum TSH receptor antibodies at 8 years of age when thyroid ultrasonography detected no nodules. After 4 years of effective treatment with thiamazole, multifocal nodules - up to 47 mm in diameter - were detected on thyroid ultrasonography. Chest CT scan revealed multiple metastatic lesions in the lung. After total thyroidectomy, PTC was pathologically diagnosed. The patient underwent two courses of radioactive iodine (RAI) treatment, but the pulmonary metastatic lesions did not take up the RAI. Molecular analyses of the PTC tissue identified a TFG/NTRK1 chimeric gene and disclosed the preserved expression of TSHR and the reduced expression of SLC5A5 compared with non-tumor thyroid tissue. CONCLUSIONS: Rapid growth and early metastasis of PTC with coexisting Graves' disease in this patient can be related to a combination of multiple factors including preserved TSHR expression, reduced SLC5A5 expression, and TFG/NTRK1 rearrangement.
Assuntos
Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Doença de Graves , Proteínas de Neoplasias , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Tomografia Computadorizada por Raios X , Adolescente , Feminino , Doença de Graves/diagnóstico por imagem , Doença de Graves/genética , Doença de Graves/metabolismo , Doença de Graves/patologia , Humanos , Metástase Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologiaRESUMO
BACKGROUND: MIRAGE syndrome, a congenital multisystem disorder due to pathogenic SAMD9 variants, describes a constellation of clinical features including 46,XY disorders of sex development (DSD), small for gestational age (SGA) and adrenal insufficiency (AI). It is poorly understood whether SAMD9 variants underlie 46,XY DSD patients born SGA (46,XY DSD SGA) without AI. This study aimed to define the frequency and phenotype of SAMD9 variants in 46,XY DSD SGA without AI. METHODS: Forty-nine Japanese patients with 46,XY DSD SGA (Quigley scale, 2 to 6; gestational age-matched birth weight percentile, <10) without history of AI were enrolled. The single coding exon of SAMD9 was PCR-amplified and sequenced for each patient. Pathogenicity of an identified variant was verified in vitro. Placenta tissues were obtained from the variant-carrying patient, as well as from another previously described patient, and were analyzed histologically. RESULTS: In one 46,XY DSD SGA patient, a novel heterozygous SAMD9 variant, p.Phe1017Val, was identified. Pathogenicity of the mutant was experimentally confirmed. In addition to DSD and SGA, the patient had neonatal thrombocytopenia, severe postnatal grow restriction, chronic diarrhea and susceptibility to infection, all features consistent with MIRAGE, leading to premature death at age 14 months. The patient did not have any manifestations or laboratory findings suggesting AI. Placenta tissues of the two variant-carrying patients were characterized by maldevelopment of distal villi without other findings of maternal underperfusion. CONCLUSIONS: MIRAGE syndrome is a rare cause of 46,XY DSD SGA without AI. This study exemplifies that AI is a common feature of MIRAGE syndrome but that the absence of AI should not rule out a diagnosis of the syndrome.