RESUMO
Biallelic loss of function mutations in the CLDN16 gene cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and chronic kidney disease. Here we report two cases of FHHNC with diverse clinical presentations and hypercalcemia in one as a novel finding. Pt#1 initially presented with urinary tract infection and failure to thrive at 5.5 months of age to another center. Bilateral nephrocalcinosis, hypercalcemia (Ca: 12.2 mg/dl), elevated parathyroid hormone (PTH) level, and hypercalciuria were detected. Persistently elevated PTH with high/normal Ca levels led to subtotal-parathyroidectomy at the age of 2.5. However, PTH levels remained elevated with progressive deterioration in renal function. At 9-year-old, she was referred to us for evaluation of hyperparathyroidism and, hypomagnesemia together with hypercalciuria, elevated PTH with normal Ca levels, and medullary nephrocalcinosis were detected. Compound heterozygosity of CLDN16 variants (c.715G>A, p.G239R; and novel c.360C>A, p.C120*) confirmed the diagnosis. Pt#2 was a 10-month-old boy, admitted with irritability and urinary crystals. Hypocalcemia, hypophosphatemia, elevated PTH and ALP, low 25(OH)D levels, and radiographic findings of rickets were detected. However, additional findings of hypercalciuria and bilateral nephrocalcinosis were inconsistent with the nutritional rickets. Low/normal serum Mg levels suggested the diagnosis of FHHNC which was confirmed genetically as a homozygous missense (c.602G > A; p.G201E) variant in CLDN16. Yet, hypocalcemia and hypomagnesemia persisted in spite of treatment. In conclusion, FHHNC may present with diverse clinical features with mild hypomagnesemia leading to secondary hyperparathyroidism with changing Ca levels from low to high. Early and accurate clinical and molecular genetic diagnosis is important for proper management.
Assuntos
Claudinas , Hipercalcemia , Hipocalcemia , Nefrocalcinose , Raquitismo , Criança , Claudinas/genética , Feminino , Humanos , Hipercalciúria/complicações , Hipercalciúria/diagnóstico , Hipercalciúria/genética , Lactente , Masculino , Mutação , Nefrocalcinose/complicações , Nefrocalcinose/diagnóstico , Nefrocalcinose/genéticaRESUMO
Vitamin D-dependent rickets type IA (VDDR-IA) is caused by biallelic mutations in CYP27B1. Data regarding genotype-phenotype correlation in VDDR-IA are scarce. Here, we aimed to investigate clinical/genotypic features and long-term follow-up of 13 new cases with VDDR-IA and genotype-phenotype correlation of reported cases in the literature. Thirteen patients with VDDR-IA were evaluated. Eight patients had reached their final height at the time of the study and, for whom, long-term outcome data were analyzed. Further, all VDDR-IA patients in the literature (n:183) were analyzed and clinical-genetic features were recorded. The median age of diagnosis was 2.55 ± 1.13 (1.0-12) years. Initial diagnoses before referral to our clinic were nutritional rickets (n:7), hypophosphatemic rickets (n:2), and pseudohypoparathyroidism (n:1). All had biochemical evidence suggestive of VDDR-IA; except one with elevated 1,25(OH)2D3 and another with hyperphosphatemia, in whom pseudohypoparathyroidism was excluded with molecular tests. Combined analyses of our cohort and other series in the literature demonstrated that three most common CYP27B1 mutations are p.F443Pfs*24, c.195 + 2T > G, and p.V88Wfs*71. In Turkish population, p.K192E mutation along with the former two is the most common mutations. Comparison of clinical features demonstrated that c.195 + 2T > G mutation causes the most severe and p.K192E mutation causes the least severe phenotype with respect to age and height at presentation and calcitriol requirement. We found a clear genotype-phenotype correlation in VDDR-IA, notably CYP27B1 intronic c.195 + 2T > G mutation causes a more severe phenotype with lower height SDS at presentation and, higher calcitriol requirement, while less severe phenotype occurs in p.K192E mutation.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Raquitismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Calcitriol , Criança , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/genética , Estudos de Associação Genética , Humanos , Lactente , Mutação , Raquitismo/genéticaRESUMO
Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.
Assuntos
Fissura Palatina/complicações , Exoftalmia/complicações , Hipofosfatemia/etiologia , Microcefalia/complicações , Osteosclerose/complicações , Anormalidades Múltiplas , Caseína Quinase I/genética , Proteínas da Matriz Extracelular/genética , Humanos , Lactente , MasculinoAssuntos
Deficiências do Desenvolvimento/etiologia , Hipertensão/etiologia , Aumento de Peso , Adolescente , Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Estatura , Deficiências do Desenvolvimento/sangue , Deficiências do Desenvolvimento/diagnóstico , Humanos , Hipertensão/sangue , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Masculino , Anamnese , Renina/sangue , Índice de Gravidade de DoençaAssuntos
Proteínas Culina/genética , Deficiências do Desenvolvimento/genética , Hipertensão/genética , Pseudo-Hipoaldosteronismo/diagnóstico , Aumento de Peso , Adolescente , Aldosterona/sangue , Estatura , Análise Mutacional de DNA , Deficiências do Desenvolvimento/sangue , Deficiências do Desenvolvimento/diagnóstico , Diagnóstico Diferencial , Diuréticos/administração & dosagem , Humanos , Hipertensão/sangue , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Masculino , Anamnese , Mutação , Potássio/sangue , Pseudo-Hipoaldosteronismo/sangue , Pseudo-Hipoaldosteronismo/complicações , Pseudo-Hipoaldosteronismo/genética , Renina/sangue , Índice de Gravidade de Doença , Tiazidas/administração & dosagemRESUMO
OBJECTIVES: Nuclear receptor subfamily 5 group A member 1 (NR5A1) is a transcription factor critical for the development of various organs. Pathogenic variants in NR5A1 are associated with a spectrum of disorders of sex development (DSD). CASE PRESENTATION: A 15-month-old baby, raised as a girl, was referred for genital swelling and ambiguous genitalia. Born to healthy consanguineous parents, the baby had a phallus, perineal hypospadias, labial fusion, and a hypoplastic scrotum. Hormonal evaluation showed normal levels, and ultrasonography revealed small gonads and absence of Müllerian derivatives. Post-human chorionic gonadotropin (hCG) testing indicated an adequate testosterone response. The karyotype was 46,XY, and in it was found a homozygous NR5A1 variant (c.307 C>T, p.Arg103Trp) in a custom 46 XY DSD gene panel. Notably, the patient exhibited complete sex reversal, hyposplenia, and no adrenal insufficiency. CONCLUSIONS: Previously, NR5A1 pathogenic variants were considered to be dominantly inherited, and homozygous cases were thought to be associated with adrenal insufficiency. Despite the homozygous pathogenic variant, our patient showed hyposplenism with normal adrenal function; this highlights the complexity of NR5A1 genotype-phenotype correlations. These patients should be monitored for adrenal insufficiency and DSD as well as splenic function.
Assuntos
Transtorno 46,XY do Desenvolvimento Sexual , Homozigoto , Fator Esteroidogênico 1 , Humanos , Fator Esteroidogênico 1/genética , Transtorno 46,XY do Desenvolvimento Sexual/genética , Feminino , Masculino , Lactente , Mutação , PrognósticoRESUMO
OBJECTIVE: Advanced glycation end products (AGEs) are irreversible macromolecules formed by nonenzymatic reactions due to chronic hyperglycemia. The aim of this study was to assess the relationship between AGEs and the microvascular complications of children and adolescents with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: Twenty-six T1DM patients with microvascular complications and 58 complication-naive patients who were similar regarding age, sex, and pubertal status enrolled in the study. Anthropometric, biochemical, ophthalmologic, and neurologic variables were compared with serum AGEs levels by the fluorescence method. RESULTS: There was no significant difference observed between the patients with complications and those without complications in terms of serum levels of AGEs and other biochemical parameters. However, the duration of T1DM and urine microalbumin-creatinine ratio (uACR) were significantly higher in the complication-positive group (P < .001). Serum levels of AGEs were found to be similar when retinopathy, peripheral, and optic neuropathy were separately compared with the complication-naive group (P > .05). However, patients with nephropathy had significantly higher serum levels of AGEs than patients without complications (P = .023). In addition, there was a significant positive correlation between serum AGEs levels and uACR (P = .042) but not other parameters (P > .05). CONCLUSION: This study is the first to evaluate the association between serum AGEs levels and microvascular complications in children and adolescents with T1DM. Our study highlights that serum AGEs levels are significantly correlated with nephropathy but not with retinopathy and neuropathy. Further long-term studies with a larger sample size are required to establish a better relationship between diabetic complications and AGEs. Cite this article as: Kirkgöz T, Acar S, Küme T, et al. Evaluation of serum advanced glycation end product levels and microvascular complications in children and adolescents with type 1 diabetes mellitus. Turk Arch Pediatr. 2024;59(1):31-37.
RESUMO
Objective: Congenital hypopituitarism (CH) is a rare disease characterized by one or more hormone deficiencies of the pituitary gland. To date, many genes have been associated with CH. In this study, we identified the allelic variant spectrum of 11 causative genes in Turkish patients with CH. Materials and methods: This study included 47 patients [21 girls (44.6%) and 26 boys (55.4%)] from 45 families. To identify the genetic etiology, we screened 11 candidate genes associated with CH using next-generation sequencing. To confirm and detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results: We identified 12 possible pathogenic variants in GHRHR, GH1, GLI2, PROP-1, POU1F1, and LHX4 in 11 patients (23.4%), of which six were novel variants: two in GHRHR, two in POU1F1, one in GLI2, and one in LHX4. In all patients, these variants were most frequently found in GLI2, followed by PROP-1 and GHRHR. Conclusion: Genetic causes were determined in only 23.4% of all patients with CH and 63% of molecularly diagnosed patients (7/11) from consanguineous families. Despite advances in genetics, we were unable to identify the genetic etiology of most patients with CH, suggesting the effect of unknown genes or environmental factors. More genetic studies are necessary to understand the etiology of CH.
Assuntos
Hipopituitarismo , Feminino , Humanos , Masculino , Alelos , Hipopituitarismo/diagnóstico , Hipopituitarismo/genética , Mutação , Proteínas Nucleares/genética , Fator de Transcrição Pit-1/genética , Fatores de Transcrição/genética , Proteína Gli2 com Dedos de Zinco/genéticaRESUMO
OBJECTIVES: Central precocious puberty (CPP) develops as a result of early stimulation of the hypothalamic-pituitary-gonadal (HPG) axis. The loss-of-function mutations in the Makorin-ring-finger3 (MKRN3) gene appear to be the most common molecular cause of familial CPP. We aimed to identify MKRN3 gene mutations in our CPP cohort and to investigate the frequency of MKRN3 mutations. METHODS: 102 patients with CPP included. 53 of them had family history of CPP in the first and/or second-degree relatives. MKRN3 gene was analyzed by next-generation sequencing. RESULTS: Possible pathogenic variants were found in 2/53 patients with family history of CPP (3.8%) and 1/49 patient without family history (2%). A novel heterozygous c.1A>G (p.Met1Val) mutation, a novel heterozygous c.683_684delCA (p.Ser228*) and a previously reported c.482dupC (Ala162Glyfs*) frameshift variations were detected. The two novel variants are predicted to be pathogenic in silico analyses. CONCLUSIONS: In our cohort, possible pathogenic variants in MKRN3 gene were detected in 2.9% of the total cohort, 3.8% of the familial and 2% of the nonfamilial cases, slightly lower than that reported in the literature. Two novel variants detected contribute to the molecular repertoire of MKRN3 defects in CPP. Classical pattern of paternal inheritance has been demonstrated in all three cases. However, the father of the patient 3 did not have history of CPP suggesting that the father inherited this variant from his mother and had phenotype skipping. Therefore, we emphasize that the absence of history of CPP in the father does not exclude the possibility of a MKRN3 mutation.
Assuntos
Puberdade Precoce , Humanos , Puberdade Precoce/genética , Ribonucleoproteínas/genética , Ubiquitina-Proteína Ligases/genética , Mutação , Mutação da Fase de Leitura , PuberdadeRESUMO
INTRODUCTION: Thyrotropin-producing pituitary adenoma (TSHoma) is a very rare disease, representing less than 1% of the pituitary tumours and presenting with elevated thyroid hormones and normal/high TSH concentrations. CASE PRESENTATION: A 7-year-old boy with nervousness was referred by his psychiatrist for elevated free T4, T3, and TSH levels. Initial evaluation revealed an elevated α-subunit. Pituitary magnetic resonance imaging (MRI) demonstrated a macroadenoma. The patient underwent a trans-sphenoidal tumour resection (TSS) which showed positive immunohistochemical staining for TSH, growth hormone, and prolactin in tumoral tissue. Euthyroidism was achieved for 1 year after TSS, then recurrence of tumour with elevated TSH and thyroid hormone levels necessitated a re-operation with TSS followed by gamma-knife radiosurgery. The euthyroid state was achieved and lasted for 2.5 years this time, but due to the recurrence, medical treatment had been commenced with cabergoline and octreotide. Euthyroidism was maintained for the last 4 years on monthly octreotide treatment. A repeat MRI demonstrated no pituitary mass, but a mass in the sphenoidal sinus had been detected. Removal of this mass by surgery did not achieve euthyroidism. 68Ga-DOTA-TATE positron emission tomography/computed tomography showed residual tissue extending from the pituitary region to the sphenoid sinus. The patient's bone age was advanced by 2 years at diagnosis which became 4 years in 1 year after the diagnosis and remained so throughout follow-up, leading to a final height of -3.3 SDS below his target height at the age of 16 years. CONCLUSION: The diagnosis, treatment, and follow-up of TSHomas are challenging, and short stature due to accelerated bone maturation is a complication of paediatric TSHomas.
Assuntos
Adenoma , Hipertireoidismo , Neoplasias Hipofisárias , Masculino , Humanos , Criança , Pré-Escolar , Adolescente , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/terapia , Octreotida , Tireotropina , Adenoma/cirurgia , Adenoma/diagnóstico , HipófiseRESUMO
The novel coronavirus disease (COVID-19) has emerged as a global pandemic. This was a prospective, case-control study conducted in Izmir, Turkey. The aim of this study was to assess the relationship between COVID-19 and new-onset T1DM. We included pediatric patients (aged 6 mo-18 yr) with new-onset type-1 diabetes mellitus (T1DM) diagnosed during the COVID-19 pandemic, between April 2020 and January 2021. Polymerase chain reaction was used to diagnose COVID-19 after hospital admission. An enzyme-linked immunoassay for IgM and IgG against SARS-CoV-2 was performed after the diagnosis was confirmed. In the control group, the blood antibody test was conducted as close as possible to the time of the T1DM patient referral. A total of 118 participants were included in the study, comprising 57 (48%) patients with new-onset T1DM and 61 (52%) healthy controls. Of the 57 patients, 36 (63.2%) presented with DKA, 17 (29.7%) with diabetic ketosis, and four (7%) incidentally. The SARS-CoV-2 antibody test was positive in five (8.7%) patients with T1DM and six (10%) controls. The rate of positivity did not differ between the two groups (p = 0.901). It was not possible to demonstrate a clear association between SARS-CoV-2 infection and new-onset T1DM. Whether SARS-CoV-2 increases susceptibility to diabetes by triggering islet cell autoimmunity and affects the timing of overt diabetes in patients with existing autoimmunity should be studied in large cohorts.
RESUMO
Dysosteosclerosis (DOS) is a rare sclerosing bone dysplasia characterized by unique osteosclerosis of the long tubular bones and platyspondyly. DOS is inherited in an autosomal recessive manner and is genetically and clinically heterogeneous. To date, four individuals with DOS who have five different TNFRSF11A mutations have been reported. Based on their data, it is hypothesized that mutations producing aberrant mutant RANK proteins (missense or truncated or elongated) cause DOS, while null mutations lead to osteopetrosis, autosomal recessive 7 (OPTB7). Herein, we present the fifth case of TNFRSF11A-associated DOS with a novel homozygous frame-shift mutation (c.19_31del; p.[Arg7CysfsTer172]). The mutation is predicted to cause nonsense mutation-mediated mRNA decay (NMD) in all RANK isoform transcripts, resulting in totally null allele. Our findings suggest genotype-phenotype relationship in TNFRSF11A-associated OPTB7 and DOS remains unclear, and that the deficiency of TNFRSF11A functions might cause DOS, rather than osteopetrosis. More data are necessary to understand the phenotypic spectrum caused by TNFRSF11A mutations.
RESUMO
Objective: To evaluate the efficacy of degludec/aspart (IDegAsp) insulin co-formulation in children and adolescents with poorly controlled type 1 diabetes (T1DM). Methods: Patients with poorly controlled T1DM on basal-bolus insulin regimes and having compliance problems related to insulin injections were switched to IDegAsp and were included. Data on hemoglobin A1c (HbA1c) levels, hypoglycemic episodes, frequency of diabetic ketoacidosis (DKA) and insulin doses were recorded at baseline and after one year of IDegAsp treatment. Results: Fifty patients (22 girls; 44%) were started on IDegAsp. The mean±standard deviation (range) age and duration of diabetes were 12.9±3.4 (4-18) and 5.2±3.1 (1.0-13.7) years, respectively. At the end of one year, 38 patients were still on IDegAsp, whereas 12 patients had opted to resume their original treatments. In those who continued on IDegAsp, HbA1c levels did not change, but the number of self-reported mild-moderate hypoglycemic episodes decreased significantly (p<0.05). In the year before switching to IDegAsp, 11 DKA attacks in 9 patients were observed, whereas this decreased to 4 DKA attacks in 4 patients after one year of IDegAsp therapy (p=0.06). Conclusion: IDegAsp regimen may improve clinical management in poorly controlled basal-bolus insulin regimen T1DM patients who have frequent hypoglycemia and DKA attacks, as well as in those with poor compliance with multiple injections. Although a simplified basal-bolus IDegAsp regimen is an attractive option for patients with T1DM, some may not adapt to this treatment due to the fixed IAsp dose of IDegAsp.
Assuntos
Diabetes Mellitus Tipo 1 , Hipoglicemia , Adolescente , Glicemia , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Hemoglobinas Glicadas , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina Aspart/uso terapêutico , Insulina de Ação Prolongada , MasculinoRESUMO
INTRODUCTION: Neonatal severe hyperparathyroidism (NSHPT) is a rare cause of neonatal hypercalcemia caused by a loss of function mutation in the calcium-sensing receptor (CaSR). Hypercalcemia in NSHPT can be life-threatening. Maintenance of serum calcium within a safe range is the primary goal of treatment through hydration, forced diuresis, and bisphosphonate treatment, nevertheless most cases require parathyroidectomy. We report a case with NSHPT diagnosed on the first day of life (DoL) and successfully treated with cinacalcet as the first-line treatment from the 2nd DoL up to the age of 18 months. CASE REPORT: A full-term baby evaluated for weight loss at postnatal 14th hour and found to have hypercalcemia (14.4 mg/dL, reference range [RR]: 8.0-11.3). Despite hydration and diuresis, hypercalcemia persisted. Further evaluation revealed a parathyroid hormone (PTH) level of 1,493 pg/mL (RR: 15-65) and urine Ca/Cr of 0.09 mg/mg (RR: 0.03-0.81). Cinacalcet treatment was initiated on the 2nd DoL with the diagnosis of NSHPT due to hypocalciuric hypercalcemia and elevated PTH level. Ca levels decreased to normal levels on the 7th DoL. She was discharged from hospital at postnatal day 15 on cinacalcet treatment and still continued at 18 months of age. Sequencing of CaSR revealed a novel homozygous c.1836G>A (p.G613E) mutation in the patient, for which the parents and sister were heterozygous. CONCLUSION: This case represents the youngest age at cinacalcet initiation and the longest duration without parathyroidectomy in a homozygous NSHPT and demonstrates that cinacalcet is an effective first-line treatment in patients who are responsive to this treatment modality and allows avoiding/delay in surgical intervention in NSHPT.
Assuntos
Calcimiméticos/administração & dosagem , Cinacalcete/administração & dosagem , Hiperparatireoidismo Primário/tratamento farmacológico , Hiperparatireoidismo Primário/genética , Doenças do Recém-Nascido/tratamento farmacológico , Doenças do Recém-Nascido/genética , Receptores de Detecção de Cálcio/genética , Feminino , Humanos , Recém-NascidoRESUMO
BACKGROUND: Besides local reactions, systemic hypersensitivity reactions such as urticaria, anaphylaxis, serum sickness and Henoch-Schönlein purpura (HSP) have been reported during gonadotropin-releasing hormone (GnRH) analogue treatment. AIM: To present the clinical presentation of 9 cases with systemic hypersensitivity reactions to GnRH analogues and discuss the management of such reactions based on our experience. PATIENTS AND METHODS: Nine of 232 (3.8%) patients with central precocious puberty receiving GnRH analogue treatment had systemic hypersensitivity reactions in 4 years' period. Six patients had a type 1 hypersensitivity reaction (generalized hives, pruritus, and/or edema) to triptorelin acetate (TA), 2 patients to leuprolide acetate (LA), and 1 patient to both medications who also developed anaphylaxis to LA during intradermal test (IDT). Another patient on TA had skin lesions suggestive of HSP. GnRH analogue treatment was discontinued in 2 patients after discussion with the parents. Treatment was changed to another GnRH analogue preparation in 6 patients and was maintained with the same medication with antihistamines and corticosteroid premedication in 1 patient. None of the patients developed new reactions after these precautions. CONCLUSION: Systemic hypersensitivity reactions should be carefully evaluated and cross-reaction to the other GnRH analogues should be kept in mind. Discontinuation of GnRH analogue is always an option. However, if continuation of GnRH analogue is elected, we recommend switching to an alternative GnRH analogue, which should be considered only after a skin prick test (SPT) and IDT. In the lack of the possibility to perform SPT and IDT, injections may be administered under strict medical supervision in a well-equipped facility to manage anaphylaxis. We discuss additional options in situations where alternative GnRH analogues are unavailable, which enabled us to continue treatment in most cases without further problems.
Assuntos
Corticosteroides/uso terapêutico , Hipersensibilidade a Drogas/tratamento farmacológico , Hipersensibilidade a Drogas/etiologia , Fármacos para a Fertilidade Feminina/efeitos adversos , Antagonistas dos Receptores Histamínicos/uso terapêutico , Leuprolida/efeitos adversos , Puberdade Precoce/tratamento farmacológico , Pamoato de Triptorrelina/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: Biallelic mutations in the TBX19 gene cause severe early-onset adrenal failure due to isolated ACTH deficiency (IAD). This rare disease is characterized by low plasma ACTH and cortisol levels, with normal secretion of other pituitary hormones. Herein, we report a patient with IAD due to a novel TBX19 gene mutation, who is also of tall stature. CASE REPORT: A 48/12-year-old girl was presented with loss of consciousness due to hypoglycemia. The patient was born at term with a birth weight of 3800 g. Her parents were first-degree cousins. She had a history of several hospitalizations for recurrent seizures, abdominal pain, and vomiting. At presentation, her weight and height were + 1.8 and + 2.2 SDS, respectively. Serum glucose was 25 mg/dl (1.4 mmol/L), with normal sodium, potassium, and insulin concentrations. The child was hypocortisolemic (0.1 µg/dl), and ACTH levels were extremely low (< 5.0 pg/ml). A diagnosis of IAD was made and hydrocortisone treatment was started. Hypoglycemic episodes, seizures, and recurrent gastrointestinal complaints disappeared after hydrocortisone replacement. Magnetic resonance imaging of the pituitary was normal. Whole exome sequencing revealed a novel homozygous c.302G > A (W101*) mutation in the TBX19 gene. CONCLUSION: We report a new mutation in the TBX19 gene in a patient with isolated ACTH deficiency. While overgrowth is a known feature of some types of adrenal insufficiencies, including MC2R gene defects and POMC deficiency, it may be a novel feature for TPIT deficiency, as in our patient.
Assuntos
Hormônio Adrenocorticotrópico/deficiência , Desenvolvimento Infantil , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Proteínas de Homeodomínio/genética , Hipoglicemia/diagnóstico , Hipoglicemia/genética , Puberdade/fisiologia , Proteínas com Domínio T/genética , Hormônio Adrenocorticotrópico/genética , Pré-Escolar , Doenças do Sistema Endócrino/complicações , Feminino , Doenças Genéticas Inatas/complicações , Predisposição Genética para Doença , Humanos , Hipoglicemia/complicações , Hipoglicemia/etiologia , Linhagem , Puberdade/genética , Maturidade Sexual/genéticaRESUMO
OBJECTIVE: Dehydroepiandrosterone (DHEA) sulfotransferase (SULT2A1) converts DHEA to DHEA sulfate (DHEAS) which prevents bioactive androgen excess. This enzymatic reaction requires PAPS (3'-phospho-adenosine-5'-phosphosulfate) biosynthesis mediated by PAPS synthase 2 (PAPSS2). Here, we report a patient presenting with short stature and premature pubarche due to a novel homozygous mutation in the PAPPS2 gene. CASE REPORT: A 7.5-year-old girl was referred for short stature. She was born at term with a birth weight of 2,850 g and her parents were first cousins. At presentation, her height was 113.0 cm (-2.1 SDS) and weight was 28.3 kg (+0.9 SDS), her arm span was 115.0 cm, and upper to lower segment ratio was 1.2. Her pubic hair and breast development were at Tanner stage III and I, respectively. Radiographs revealed mild lumbar scoliosis and platyspondyly and irregular vertebral endplates in the thoracolumbar region. Her serum DHEAS was low (39 ng/mL). The plasma DHEAS/DHEA ratio was significantly decreased on 2 separate measurements (4.4 and 19.8; normal range 31-345). PAPSS2 gene analysis identified a homozygous p.L440Wfs*12 (c.1318_1330 delCTACTACACCCTC) variant. This is the first report of a large deletion leading to a frameshift effect in the PAPSS2 gene and a truncated PAPSS2 protein. CONCLUSION: We describe the third case with PAPSS2 deficiency presenting with premature pubarche, and the first large deletion in the PAPSS2 gene. Although PAPSS2 deficiency is a rare cause of premature pubarche and adrenal androgen excess, it should be considered, especially in cases with disproportionate short stature and clinical hyperandrogenism associated with low plasma DHEAS concentration.
Assuntos
Transtornos do Crescimento/sangue , Complexos Multienzimáticos/genética , Mutação , Puberdade Precoce/sangue , Sulfato Adenililtransferase/genética , Sulfato de Desidroepiandrosterona/sangue , Feminino , Transtornos do Crescimento/genética , Humanos , Puberdade Precoce/genéticaRESUMO
Homozygous loss of function mutations in genes encoding anti-Müllerian hormone (AMH) or its receptor (AMHRII) lead to persistent Müllerian duct syndrome (PMDS). PMDS is characterized by the presence of a uterus, fallopian tubes, cervix, and upper vagina in fully virilised 46,XY males. Both surgical management and long-term follow-up of these patients are challenging. Four cases with PMDS presented with cryptorchidism and inguinal hernia, and laparoscopic inguinal exploration revealed Müllerian remnants. Three of the patients had homozygous mutations in the AMH gene, one with a novel c.1673G>A (p.Gly558Asp) mutation, and one patient had an AMHRII mutation. All patients underwent a single-stage laparotomy in which the fundus of the uterus was split along the midline to release testes and to avoid damaging the vas deferens or the deferential artery. Biopsy of Müllerian remnants did not reveal any malignancy. The cases presented here expand the clinical and molecular presentation of PMDS. Cryptorchidism and inguinal hernia in the presence of Müllerian structures in an appropriately virilised 46,XY individual should suggest PMDS. Long-term reproductive and endocrinological surveillance is necessary.
RESUMO
Primary adrenal insufficiency (PAI) is a life-threatening disorder of adrenal cortex which is characterized by deficient biosynthesis of glucocorticoids, with or without deficiency in mineralocorticoids and adrenal androgens. Typical manifestations of primary adrenal insufficiency include hyperpigmentation, hypotension, hypoglycaemia, hyponatremia with or without hyperkalemia that are generally preceded by nonspecific symptoms at the onset. Recessively inherited monogenic disorders constitute the largest group of primary adrenal insufficiency in children. The diagnostic process of primary adrenal insufficiency includes demonstration of low cortisol concentrations along with high plasma ACTH and identifying the cause of the disorder. Specific molecular diagnosis is achieved in more than 80% of children with PAI by detailed clinical and biochemical characterization integrated with advanced molecular tools. Hormone replacement therapy determined on the type and the severity of deficient adrenocortical hormones is the mainstay of treatment. Optimized methods of steroid hormone delivery, improved monitoring of hormone replacement along with intensive education of patients and families on the rules during intercurrent illness and stress will significantly reduce the morbidity and mortality associated with primary adrenal insufficiency.
Assuntos
Insuficiência Adrenal/diagnóstico , Glucocorticoides/uso terapêutico , Terapia de Reposição Hormonal , Mineralocorticoides/uso terapêutico , Insuficiência Adrenal/sangue , Insuficiência Adrenal/tratamento farmacológico , Hormônio Adrenocorticotrópico/sangue , Criança , Humanos , Hidrocortisona/sangueRESUMO
Background. Acute otitis media [AOM] may affect the accuracy of tympanic temperature measurements. We aimed to compare tympanic temperature measurements in patients with AOM against control groups, as well as compare the tympanic temperatures with axillary thermometry. Methods. This is a prospective, observational study. Patients from pediatric outpatient and emergency clinics who were diagnosed as single-sided AOM were included consecutively in the study. Normal ears of patients and children having the same age and gender who were not diagnosed as AOM were also studied as controls. Results. In patients with AOM, infected ears had higher temperatures than normal ears with a mean of 0.48 ± 0.01°C. There was no significant difference between the right and left tympanic temperatures in control group. Compared with axillary temperature, the sensitivity of tympanic temperature in the infected ear was 91.7% and the specificity was 74.8%. Conclusion. Comparisons of axillary and tympanic temperatures in children with AOM during the active infection concluded higher tympanic temperatures in infected ears. We suggest that the higher tympanic temperatures, approximately 0.5°C in our study, in infected ears may aid in diagnosis of patients with fever without a source in pediatric clinics.