Mortality is high in pediatric acute lung injury/acute respiratory distress syndrome. Mechanical ventilation-associated risk factors for death among such patients are potential targets for intervention.
Background: Idiopathic central precocious puberty (CPP) is mostly described as an isolated entity. A few studies have shown its association with clinical syndromes and rare cases of chromosomal abnormalities. Objective: To clinically characterize and to genetically investigate a cohort of patients with CPP associated with complex phenotypes. Patients and methods: Two hundred patients with idiopathic CPP were retrospectively evaluated, including phenotypic, metabolic and hormonal characterization. Thirty-two of them presented at least 3 other clinical features and conditions, characterizing complex phenotypes. Genomic microarray was performed in all sporadic and index cases, and MLPA and whole-exome sequencing were performed in a subset of cases. Results: In the group of 32 idiopathic CPP patients with complex phenotypes (28 girls, 4 boys; 16 sporadic, 16 familial), mean age at puberty onset was 6.2 yr (±1.9) for girls and 8 yr (±0.1) for boys. There was a wide phenotypic spectrum. The more prevalent clinical features described included metabolic, neurocognitive and growth phenotypes; less prevalent features included dysmorphic features and congenital anomalies. Genetic investigation resulted as follows: 3 sporadic cases with maternal uniparental disomy of chromosome 14 (Temple syndrome), with disruption at the imprinted locus of DLK1 ; 1 sporadic patient with a 7q11.23 deletion (Williams syndrome); 7 patients from 3 unrelated families with Xp22.33 deletions, including SHOX , upstream regulatory regions, and 3 other coding-genes. Moreover, whole-exome sequencing analysis revealed candidate pathogenic variants in 2 CPP cases. One girl with sporadic CPP associated with imperforate anus and learning difficulties presented rare frameshift variants in a dominant de novo mode in 2 genes: AREL1 (14:75142990; p.S229fs) coding an ubiquitin ligase; and TNRC6B (22:40662223-40662224; p.S663fs) coding a molecule with a role in RNA-mediated gene silencing. Both genes are expressed in hypothalamus. In addition, one boy with maternal familial CPP and autism had 2 rare potentially pathogenic variants in a dominant autosomal inheritance mode: a frameshift deletion in MKKS (20:10393728-10393731; p.F144fs) coding a protein with a role in cytokinesis; and a missense variant (4:70359481; p.P267L) in UGT2B4 , coding a protein involved in estrogen hydroxylation and related to menarche timing in genome-wide association studies. Conclusion: CPP might be associated with additional clinical conditions, characterizing complex phenotypes. Two chromosomal regions, Xp22.33 and 7q11.23, represent novel candidate loci implicated in CPP. In addition, distinct novel genetic abnormalities were identified in CPP patients with complex phenotypes.
Objectives Longer-acting gonadotropin-releasing hormone analogs (GnRHa) have been widely used for central precocious puberty (CPP) treatment. However, the follow-up of patients after this treatment are still scarce. Our aim was to describe anthropometric, metabolic, and reproductive follow-up of CPP patients after treatment with leuprorelin acetate 3-month depot (11.25 mg). Methods Twenty-two female patients with idiopathic CPP were treated with leuprorelin acetate 3-month depot (11.25 mg). Their medical records were retrospectively evaluated regarding clinical, hormonal, and imaging aspects before, during, and after GnRHa treatment until adult height (AH). Results At the diagnosis of CPP, the mean chronological age (CA) was 8.2 ± 1.13 year, and mean bone age (BA) was 10.4 ± 1.4 year. Mean height SDS at the start and the end of GnRHa treatment was 1.6 ± 0.8 and 1.3 ± 0.9, respectively. The mean duration of GnRHa treatment was 2.8 ± 0.8 year. Mean predicted adult heights (PAH) at the start and the end of GnRH treatment was 153.2 ± 8.6 and 164.4 ± 7.3 cm, respectively (p<0.05). The mean AH was 163.2 ± 6.2 cm (mean SDS: 0.1 ± 1). All patients were within their target height (TH) range. There was a decrease in the percentage of overweight and obesity from the diagnosis until AH (39–19% p>0.05). At the AH, the insulin resistance and high LDL levels were identified in 3/17 patients (17.6%) and 2/21 patients (9.5%), respectively. The mean CA of menarche was 12.2 ± 0.5 years. At the AH, PCOS was diagnosed in one patient (4.8%). Conclusions Long-term anthropometric, metabolic, and reproductive follow-up of patients with CPP treated with longer-acting GnRHa revealed effectivity, safety, and favorable outcomes.
SUMÁRIOA incidência de polineuropatia em indivíduos com hipotireoidismo não é precisamente conhecida, mas alguns estudos relatam que cerca de 25% a 42% dos pacientes podem apresentar sinais clínicos neuropáticos. A seguir, relataremos um caso de síndrome poliglandular autoimune tipo 2 (SPA-2), cuja apresentação inicial foi uma polineuropatia hipotireóidea. Homem de 41 anos com queixas de parestesias e fraqueza lentamente progressiva acometendo os quatro membros associadas a sonolência frequente, astenia, intolerância ao frio, vertigens, náuseas e avidez por sal. O exame físico geral evidenciava hiperpigmentação de pele e mucosas, além de hipotensão. O exame neurológico demonstrou apenas hiporreflexia profunda global e simé-trica com discretos sinais de hipoestesia superficial em extremidades dos membros. O estudo eletroneuromiográfico (ENMG), juntamente com a avaliação laboratorial, confirmou a suspeita de tireoidite de Hashimoto associada à doença de Addison, caracterizando o quadro de SPA-2. O paciente foi tratado com fludrocortisona 0,05 mg/dia e levotiroxina 100 mcg/dia e apresentou resolução gradual e completa das queixas e das alterações encontradas nos exames físico geral e neurológico. O ENMG, repetido após seis meses, evidenciou resolução completa do quadro neuropático. Este relato mostra um caso raro de SPA-2 apresentando-se como uma polineuropatia hipotireóidea e reforça a relevância da dosagem de hormônios tireoideanos em síndromes polineuropáticas. A reposição de levotiroxina mostrou-se efetiva em reverter o quadro clínico e eletrofisiológico da neuropatia. Arq Bras Endocrinol Metab. 2014;58(3):308-12 SUMMARYThe incidence of polyneuropathy in patients with hypothyroidism is not precisely known, but some studies report that about 25% to 42% of patients may show neuropathic clinical signs. We report a case of autoimmune poliglandular syndrome type 2 (APS-2), whose initial presentation was hypothyroid polyneuropathy. A 41-year-old man complained of slowly progressive paresthesias and weakness affecting all four limbs, and associated with frequent drowsiness, weakness, cold intolerance, dizziness, nausea, and craving for salt. General physical examination showed hyperpigmentation of skin and mucous membranes, and hypotension. Neurological examination showed global, deep, and symmetrical hyporeflexia with slight signs of superficial hypoesthesia in the limbs. Electrodiagnostic studies (ENMG) together with laboratory tests, confirmed the suspicion of Hashimoto's thyroiditis associated with Addison's disease featuring the picture of APS-2. The patient was treated with fludrocortisone 0.05 mg/day and levothyroxine 100 mcg/day, and showed gradual and complete resolution of complaints. Changes were found in general physical and neurological examinations. ENMG repeated six months later showed complete resolution of neuropathy. This report shows a rare case of APS-2 presented as polyneuropathy hypothyroidism, and reinforces the importance of dosing thyroid hormone in polyneuropathy syndromes. Levothyroxine repl...
Context: The clinical recognition of familial central precocious puberty (CPP) has significantly increased in the last years. This fact can be related to the recent descriptions of genetic causes associated with this pediatric condition, such as loss-of-function mutations of two imprinted genes (MKRN3 and DLK1). Inherited defects in both genes cause paternally inherited CPP. However, no genetic abnormality has been described in families with maternally inherited CPP so far. Objectives: To characterize the clinical and genetic features of several families with maternally inherited CPP. Setting and Participants: We analyzed clinical and genetic features of children with familial CPP. No brain MRI alterations were detected in the selected patients with CPP. MKRN3 and DLK1 pathogenic mutations were excluded. Whole-exome sequencing was performed in selected cases. Results: We studied 177 children from 141 families with familial CPP. Paternal inheritance was evidenced in 44 families (31%), whereas 58 (41%) had maternally inheritance. Indeterminate inheritance was detected in the remaining families. Maternally inherited CPP affected mainly female patients (69 girls and two boys). Thelarche occurred at mean age of 6.1 ± 1.9 years in this female group. Most of girls had Tanner 3 (41%) and Tanner 4 (35%) breast development at first evaluation. One boy had additional syndromic features (macrosomia, autism, bilateral eyelid ptosis, high arcade palate, irregular teeth and abnormal gait). The pedigree analysis of patients with maternally inherited CPP revealed the following affected family members: 42 mothers, 10 grandmothers, 11 sisters, 12 aunts, and 11 female cousins. Most of the families (41) had two affected consecutive generations, while eight families had three affected generations. No consanguinity was referred. Ongoing molecular analysis revealed two rare heterozygous variants in the boy with syndromic CPP and three affected family members with precocious menarche (mother, maternally half-sister, and maternally aunt): a frameshift deletion (p.F144fs) in MKKS; and a missense variant (p.P267L) in UGT2B4, which encodes a protein involved in estrogen hydroxylation and it was related to menarche timing in genome-wide association studies. Conclusions: Maternally inherited CPP was diagnosed mainly in girls, who had thelarche at mean age of 6 years old. Dominant pattern of inheritance was more prevalent, with direct maternal transmission in 72% of the studied families. New candidate genes might be implicated with maternally inherited CPP.
Context: Loss-of-function mutations in the maternally imprinted Makorin RING-finger 3 (MKRN3) gene (15q11.2) are the most prevalent cause of familial central precocious puberty (CPP). Objectives: To analyze the phenotypes of a large cohort of children with CPP due to MKRN3 mutations and to compare them with the phenotypes of idiopathic CPP. Setting and Participants: We studied 73 individuals from 37 families with mutations in MKRN3 originating from nine different countries. The phenotypes of these patients at initial diagnosis were compared to a cohort of 124 patients with idiopathic CPP. Additionally, expression of nine different genes implicated with pubertal timing, including MKRN3, was performed in the hypothalamus of female mice in different phases of sexual maturation. Results: Nineteen different heterozygous, paternally inherited mutations in MKRN3 were identified in 73 patients with CPP (48 girls and 25 boys). Six MKRN3 mutations were frameshifts, one introduced a premature stop codon, 11 were missense mutations predicted to be pathogenic, and one was a deletion in the promoter region. A frameshift mutation affecting codon 161 in the amino terminal region of the protein was the most frequent MKRN3 defect (46%), representing a hotspot region. Among the cohort with MKRN3 mutations, first pubertal signs occurred at 6·2 ± 1·2 years in girls and 7·6 ± 1·4 years in boys. Patients harboring severe frameshift/nonsense mutations did not differ significantly in any clinical or hormonal parameters compared to the 20 patients with missense variants. However, when the 48 girls with MKRN3 mutations were compared with 124 idiopathic CPP girls, some parameters could be considered as possible predictors of the genetic cause: a lower age at first medical appointment (7·1 ± 1·1 in the MKRN3 group vs. 8·0 ± 2 years in the idiopathic group; p< 0.001) and a shorter time interval between puberty onset and medical assistance (0·8 ± 0·8 vs 2·2 ± 2·1 years; p< 0.001). Interestingly, the other predictor of MKRN3 mutations was a higher basal FSH level (5·1 ± 2·3 vs 3·9 ± 2·7 IU/L; p = 0.017) at first evaluation, although no cutoff value yielded good accuracy. Patients originating from European/Mediterranean countries were more likely to have missense variants (56% of all mutations) than North American and South American (23%) counterparts (p <0.001). Mouse Mkrn3 mRNA levels in the arcuate nucleus were highest in the prepubertal phase when compared with expression of other genes and Mkrn3 decreased progressively through puberty and adult ages. Conclusions: Different types of loss-of-function MKRN3 mutations were associated with premature sexual development in both sexes. Their phenotypes were relatively uniform, regardless of the mutation type. Clinical features of children with MKRN3 mutations were similar to the idiopathic CPP group.
Background: The laboratory evaluation of patients with precocious puberty is useful to differentiate central precocious puberty (CPP) from isolated thelarche (IPT) and peripheral precocious puberty (PPP). Ultrasensitive immunoassays, such as electrochemiluminescence (ECLIA), improved sensitivity and specificity of basal and GnRH-stimulated LH levels to establish the differential diagnosis among these conditions. Aim: To establish the diagnostic value of basal and GnRHa-stimulated LH values and basal estradiol assessed by ECLIA in pubertal disorders. Patients and Methods: We included 38 girls with pubertal disorders (28 CPP, 8 IPT, and 2 PPP). Their medical records were systematically revised. Clinical and hormonal data [basal and GnRH analog -stimulated LH levels (2 hs after leuprorrelin 3.75 mg) and basal estradiol] were analyzed. Gonadotropins and estradiol levels were assessed by ECLIA (Roche, Cobas e 6000). The functional sensitivity of the assays was 0.15 IU/L for LH, FSH 0.6 IU/L for FSH and 17 pg/mL for estradiol. Basal gonadotropins and estradiol were also assessed in a control group composed by 16 prepubertal and 19 pubertal girls. The cutoff values for basal and GnRH analog- stimulated LH for diagnosis of CPP was set at < 0.3 IU/L and 8 IU/L, respectively (1). Results: The mean age of girl with CPP, IPT, and PPP at the first clinical visit was 8 ± 0.9yr (5.25- 9.6 yr), 4.25± 2.6 (0.7-7.8 yr), and 5.12±2.9 (3.1 -7.1 yr), respectively. All CPP girls presented breast development ranging from B2 to B5, whereas IPT group B2-B4 and PPP group (B2). Pubarche was presented in 86% of girls with CPP (PH 2- PH 5). Only one girl in IPT group also presented pubarche (PH3), associated to zinc oxide cream use and none in PPP group presented pubarche. The mean basal LH was 3.4 ± 1.6 (<0.1- 8.6 IU/L), 0.15 ± 0.03 (< 0.15-0.2 IU/L), and <0.15 IU/L for CPP, IPT, and PPP, respectively. In CPP group, GnRHa- stimulated LH and basal estradiol levels were 6 ± 2.8 (4-61.4 IU/L) and 21 ± 17 (<17- 90 pg/ml), respectively. The sensitivity and specificity of basal and GnRHa-stimulated LH values for diagnosis of CPP was 64.7 % and 100%, respectively. However, the cutoff of 5 IU/L for GnRHa-stimulated LH improved sensitivity to 87.5% but with lower specificity of 67%. Estradiol was undetectable (<17 pg/ml) in 48% girls with CPP. In the IPT and PPP groups, basal LH <0.3 IU/L was detected in all patients. In the control group, all but one prepubertal girl had basal LH <0.15 IU/L. In addition, basal estradiol > 17 pg/ml was present in two girls from control prepubertal group. In the control pubertal group (B3-B4), mean basal LH was 4.2± 2.3 (<015- 8.8 IU/L) and basal estradiol was 61 ± 34 (<17-135pg/mL). Conclusion: The diagnostic value of basal and GnRH-stimulated LH levels assessed by ECLIA to diagnosis CPP is limited and must be interpreted together with clinical data. Reference: (1) Freire AV et al, Clin Endocrinol (Oxf), 2013.
Background: Central precocious puberty (CPP) is mostly described as an isolated entity. Few studies have shown an association of CPP with complex cases or genetic syndromes, but without making inferences on molecular causalities. Objective: To genetically investigate a cohort of patients with CPP associated with complex phenotypes using high throughput methodologies. Patients and methods: From a large cohort of patients with idiopathic CPP followed at a university hospital outpatient clinic, thirty-eight patients were selected for high throughput genetic investigation for presenting at least 3 additional clinical features and conditions, characterizing complex phenotypes. All had normal brain MRI. Pathogenic allelic variants in CPP known genes were initially excluded. All patients were submitted to genomic microarray (SNP or CGH arrays). A subset of patients was also submitted to whole-exome sequencing (11 cases) or target panel sequencing (18 cases). Results: Among the group of 38 patients (35 girls, 4 boys; 21 sporadic, 17 familial), mean age at puberty onset was 5.8 ±2.1 and 8.3 ±3.0 yr in girls and boys, respectively. The more prevalent clinical features described included metabolic, growth and neurocognitive phenotypes; less prevalent features included dysmorphic features and congenital anomalies. Pathogenic or probably pathogenic genetic defects were identified in 9 cases: 5 sporadic (all identified as de novo) and 4 familial. Defects in sporadic cases were as follows: three cases with 7q11.23 deletion (Williams syndrome); one girl with ventricular arrhythmia presenting a rare 1p31.3 duplication, involving NFIA gene coding a transcription factor of NFI family with hypothalamic expression; and one girl with imperforate anus and learning difficulties with rare frameshift variants in AREL1 gene (p.Ser229Aspfs*3) coding an ubiquitin ligase, and TNRC6B gene (p.Gly665Leufs*35) coding a regulator of translational inhibition. In the four familial cases, the genetic defects segregated with CPP in a dominant inheritance mode. Three cases from unrelated families presented growth phenotypes and Xp22.33 deletions, including SHOX gene and other elements. One boy with maternal familial CPP and autism had two rare potentially pathogenic variants: a frameshift deletion in MKKS gene (p.Phe144Leufs*14); and a missense variant (p.Pro267Leu) in UGT2B4 gene. Interestingly, the later gene encodes a protein involved in estrogen hydroxylation and is associated to menarche timing in GWAS. Conclusion: Novel genetic defects were identified in 23% cases of CPP associated with complex phenotypes. Three chromosomal regions represented loci potentially implicated in CPP: Xp22.33, 7q11.23 and 1p31.3. Five genes were identified as candidate genes associated with CPP: NFIA, AREL1, TNRC6B, MKKS and UGT2B4.
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