RESUMO
Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. IKZF1 and PAX5, transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced TCF3, a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children's Cancer Study Group (TCCSG) were examined. As a TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.
Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Criança , Humanos , Estudo de Associação Genômica Ampla , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Fatores de Transcrição/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genéticaRESUMO
Inherited genetic variation is associated with 6-mercaptopurine (6-MP) dose reduction and frequent toxicities induced by 6-MP. However, the tolerable dose for 6-MP is not fully predicted by the known variation in NUDT15 and TPMT among Asian children with acute lymphoblastic leukaemia (ALL). We performed a genome-wide association study (GWAS) related to 6-MP dose among Japanese children with ALL. This GWAS comprised 224 patients previously enrolled in Tokyo Children's Cancer Study Group clinical studies with replication attempted in 55 patients. Genome-wide single nucleotide polymorphism (SNP) genotypes were evaluated for association with average 6-MP dose during the initial 168 days of maintenance therapy. Possible associations were observed across five gene-coding regions, among which only variants at 13q14.2 were significant and replicated genome-wide (rs116855232, NUDT15, ß = -10.99, p = 3.7 × 10-13 ). Notable findings were observed for variants in AFF3 (rs75364948, p = 2.05 × 10-6 ) and CHST11 (rs1148407, p = 2.09 × 10-6 ), but were not replicated possibly due to small numbers. A previously reported candidate SNP in MTHFR was associated with higher average 6-MP dose (rs1801133, p = 0.045), and FOLH1 (rs12574928) was associated in an evaluation of candidate regions (padjust = 0.013). This study provides strong evidence that rs116855232 in NUDT15 is the genetic factor predominantly associated with 6-MP tolerable dose in children in Japan.
Assuntos
Mercaptopurina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Pirofosfatases , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Estudo de Associação Genômica Ampla , Humanos , Japão , Mercaptopurina/uso terapêutico , Metiltransferases/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirofosfatases/genéticaRESUMO
The survival rate of children with acute lymphoblastic leukemia (ALL) has increased to approximately 90% after substantial progress in risk-oriented treatment strategies. Between 2005 and 2013, the Tokyo Children's Cancer Study Group (TCCSG) conducted a risk-oriented, non-randomized study, L04-16. The principal aim of this study was to assemble background characteristics and treatment outcomes, and gather genetic information on leukemic cells under central diagnosis. This report outlines the background characteristics and treatment outcomes of 1033 children with ALL treated according to a TCCSG platform. The 5-year event-free and overall survival (OS) rates for all children were 78.1 ± 1.3 and 89.6 ± 1.0%, respectively. The OS rate was significantly higher in children with B-cell precursor (BCP)-ALL (91.9 ± 1.0%, n = 916) than in those with T-ALL (71.9 ± 4.3%, n = 117, p < 0.001). In univariate analysis for BCP-ALL, children aged 1-6 years (5y-OS: 94.2 ± 1.0%), with an initial white blood cell count of < 20,000/µL (94.0 ± 1.0%), high hyperdiploidy (95.4 ± 1.6%), ETV6-RUNX1 (97.4 ± 1.2%) or TCF3-PBX1 (96.9 ± 2.1%), and "Day8NoBlasts" (96.4 ± 1.1%) had the best outcomes. Genetic investigation revealed two novel fusion genes within this cohort: ETV6-ZNF385A and ZNF362-TCF4. Our study highlighted the clinical aspects of genomic features of ALL in Japanese children. We provide fundamental information for the further molecular investigation of this disease.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Análise de Variância , Povo Asiático , Linfócitos B , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Diploide , Feminino , Fusão Gênica , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Taxa de Sobrevida , Linfócitos T , Tóquio , Fator de Transcrição 4/genética , Resultado do Tratamento , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Genome-wide association studies (GWAS) performed mostly in populations of European and Hispanic ancestry have confirmed an inherited genetic basis for childhood acute lymphoblastic leukemia (ALL), but these associations are less clear in other races/ethnicities. DNA samples from ALL patients (aged 0-19 years) previously enrolled onto a Tokyo Children's Cancer Study Group trial were collected during 2013-2015, and underwent single nucleotide polymorphism (SNP) microarray genotyping resulting in 527 B-cell ALL for analysis. Cases and control data for 3,882 samples from the Nagahama Study Group and Aichi Cancer Center Study were combined, and association analyses across 10 previous GWAS-identified regions were performed after targeted SNP imputation. Linkage disequilibrium (LD) patterns in Japanese and other populations were evaluated using the varLD score based on 1000 Genomes data. Risk associations for ARID5B (rs10821936, OR = 1.84, P = 6 × 10-17) and PIP4K2A (rs7088318, OR = 0.76, P = 2 × 10-4) directly transferred to Japanese, and the IKZF1 association was detected by an alternate SNP (rs1451367, OR = 1.52, P = 2 × 10-6). Marked regional LD differences between Japanese and Europeans was observed for most of the remaining loci for which associations did not transfer, including CEBPE, CDKN2A, CDKN2B, and ELK3. This study represents a first step towards characterizing the role of genetic susceptibility in childhood ALL risk in Japanese.
Assuntos
Povo Asiático/genética , Predisposição Genética para Doença , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Fator de Transcrição Ikaros/genética , Lactente , Recém-Nascido , Japão , Desequilíbrio de Ligação , Masculino , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Transcrição/genética , Adulto JovemRESUMO
MYH9 disorder is characterized by large platelets and granulocyte inclusion bodies, and can be complicated with young-adult onsets of nephropathy, sensorineural hearing loss, and cataracts. Congenital cataracts in patients with MYH9 disorder is rare, and their etiology has not been elucidated. We report a 3-year-old patient with MYH9 disorder who had a p.E1066_A1072del mutation and developed cataracts congenitally. A review of the literature reveals that patients with an MYH9 exon 24 indel mutation, including p.E1066_A1072del, are susceptible to developing congenital cataracts and should be followed closely for other nonhematological complications.
Assuntos
Catarata/congênito , Granulócitos/ultraestrutura , Mutação INDEL , Proteínas Motores Moleculares/genética , Cadeias Pesadas de Miosina/genética , Trombocitopenia/complicações , Plaquetas/patologia , Catarata/genética , Pré-Escolar , Éxons , Granulócitos/patologia , Perda Auditiva Neurossensorial , Humanos , Corpos de Inclusão/patologia , Fenótipo , Trombocitopenia/congênito , Trombocitopenia/etiologiaAssuntos
Síndrome de Sweet/diagnóstico , Exantema/etiologia , Feminino , Humanos , Lactente , Pele/patologiaRESUMO
Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common subtype of infectious pediatric encephalopathy in Japan. The exact pathogenesis of and the best therapeutic strategy for AESD are uncertain. We firstly performed a brain biopsy in a 2-year-old boy with AESD associated with RS viral infection, which revealed activated ameoboid microglia accumulation around degenerated neuron, and astrogliosis in the affected cortex. Glutamate released from activated microglia may play an important role in the pathogenesis of AESD, which is compatible with the previous report of magnetic resonance spectroscopy showing elevated glutamate.
Assuntos
Encefalopatias/patologia , Encéfalo/patologia , Microglia/patologia , Convulsões/patologia , Biópsia , Encéfalo/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Encefalopatias/tratamento farmacológico , Encefalopatias/cirurgia , Pré-Escolar , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética , Humanos , Masculino , Convulsões/diagnóstico por imagem , Convulsões/tratamento farmacológico , Convulsões/cirurgiaRESUMO
Residual disease (RD) after induction chemotherapy may predict clinical outcome in acute myeloid leukemia (AML). In the present study, we investigated the prognostic significance of RD detected by multidimensional flow cytometry (MDF) among 34 children treated for AML in a clinical trial (JPLSG AML-05) in Japan. Bone marrow samples were analyzed at the points of the end of the first induction course (BMA-1) and second induction course (BMA-2) by MDF. RD was evaluated by detecting the immature cells showing abnormal antigen expression pattern; CD34(+), CD15(+), CD7(+). Thirteen (39.4 %) of 34 patients at BMA-1 and 8 (27.6 %) of 34 at BMA-2 had RD levels ≥0.1 %. There was no significant difference in 3y-EFS and 3y-OS between patients with RD levels ≥0.1 % and those with RD levels <0.1 % (53.8 versus 70.0 %, P = 0.30 and 50.0 versus 66.7 %, P = 0.27, respectively). However, IR cytogenetics and negative FLT3-ITD patients with RD levels ≥0.1 % exhibited significantly lower 3y-EFS and 3y-OS than those with RD levels <0.1 % (33.3 versus 83.3 %, P = 0.02 and 20.0 versus 76.9 %, P = 0.005, respectively). Our study suggests that RD shows prognostic relevance in pediatric patients with IR cytogenetics and negative FLT3-ITD AML.
Assuntos
Medula Óssea/patologia , Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Medula Óssea/metabolismo , Criança , Pré-Escolar , Aberrações Cromossômicas , Análise Citogenética , Feminino , Citometria de Fluxo , Duplicação Gênica , Humanos , Quimioterapia de Indução , Lactente , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Neoplasia Residual/genética , PrognósticoRESUMO
There is no standard treatment for adolescents aged 15 years or older with acute lymphoblastic leukemia (ALL), although this age group has been reported as having a poorer prognosis compared to younger patients. We retrospectively analyzed the outcomes of three consecutive Tokyo Children's Cancer Study Group ALL trials (1995-2006) of 373 patients aged 10 years or older, with particular focus on adolescents aged 15-18 years (older-adolescents n = 41), compared to those aged 10-14 years (younger-adolescents n = 332). The probability of event-free survival at 8 years was 67.5 ± 7.4 % for the older-adolescents and 66.5 ± 2.6 % for the younger-adolescents (p = 0.95). Overall survival was 70.7 ± 7.1 % for the older-adolescents and 74.3 ± 2.4 % for the younger-adolescents (p = 0.48). The differences between groups in relapse incidence, non-relapse mortality, and death rate during induction were not statistically significant, although the older-adolescents trended towards a higher frequency of having stem-cell transplantation during the first remission. In conclusion, our treatment strategy, which consists of intensive induction and block-type consolidation, provided improved outcomes for patients aged 15-18 years, comparable to those for patients aged 10-14 years.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Recidiva , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Resultado do TratamentoRESUMO
By the age of two years, almost all infants are infected with the Respiratory syncytial virus (RSV). One of the main causes of hospitalizations for bronchiolitis and pneumonia at this age is RSV infection. In addition to well-known risks for severe RSV disease, such as prematurity, bronchopulmonary dysplasia and congenital heart disease, immunodeficiencies, chromosomal abnormalities such as Down's syndrome or neuromuscular diseases have also been identified as risks. While the medical needs for RSV prevention in these risk groups are high, clinical evidence to support this is limited. Palivizumab was recently approved in Japan for prophylaxis in children with immunodeficiency or Down's syndrome. A clinical guidance protocol for the prevention of RSV infection using Palivizumab in these risk groups is provided here on the basis of a review of the available literature and on expert opinion. Thus, the present article reviews the published literature related to RSV infections in infants and children with immunodeficiencies or Down's syndrome in order to outline the risks, pathology and physiology of severe RSV disease in these patient groups. The purpose of this article is to facilitate understanding of the medical scientific bases for the clinical guidance.
Assuntos
Síndrome de Down/complicações , Síndromes de Imunodeficiência/complicações , Infecções por Vírus Respiratório Sincicial , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Criança , Pré-Escolar , Humanos , Hospedeiro Imunocomprometido , Lactente , Recém-Nascido , Controle de Infecções , Palivizumab , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Fatores de RiscoRESUMO
Streptococcus gallolyticus subsp. pasteurianus was formerly classified as S. bovis biotype II/2, which is recognized as a rare cause of neonatal sepsis and meningitis. Since the taxonomy classification change, there have not been many reports of meningitis due to S. gallolyticus subsp. pasteurianus. Moreover, the pathogenesis of late onset S. gallolyticus subsp. pasteurianus meningitis in infants is unclear. Here we report a case of meningitis in a 5-week-old infant with preceding diarrhea. S. bovis biotype II/2 was isolated from the blood, cerebrospinal fluid and stool, and then was identified as S. gallolyticus subsp. pasteurianus on 16S rRNA gene sequencing. Isolates from all three sample types had identical profiles on pulsed-field gel electrophoresis. The intestinal tract was thought to be the source of the infection.
Assuntos
Meningites Bacterianas , Infecções Estreptocócicas , Sequência de Bases , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Streptococcus/classificação , Streptococcus/genéticaRESUMO
Immediate allergy to l-asparaginase (ASP) is a major obstacle in treating lymphoid malignancies. ASP-specific immunoglobulin G (ASP-IgG) has been used as a surrogate marker. Recently, the CD203c-basophil activation test (BAT) was found to be useful in diagnosing IgE-mediated allergies. We compared the diagnostic utility of the CD203c-BAT to that of ASP-IgG levels in determining ASP allergies in children. Eight ASP allergic reactions occurred over 75 ASP treatment courses. The sensitivity, specificity and area under the receiver operating characteristic curve of CD203c-BAT were similar to the ASP-IgG levels (0.75 vs. 0.85, 0.82 vs. 0.78 and 0.81 vs. 0.85, respectively). Positive skin prick test results in patients with ASP allergy suggested that ASP-IgE was one of the key players in ASP allergy. A combination of the BAT with the ASP-IgG level had the highest specificity (0.95) and positive predictive value (0.62), which permitted us to identify ASP allergy more effectively.
Assuntos
Asparaginase/imunologia , Basófilos/imunologia , Basófilos/metabolismo , Hipersensibilidade Imediata/imunologia , Hipersensibilidade Imediata/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , Adolescente , Biomarcadores/sangue , Biomarcadores/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade Imediata/diagnóstico , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lactente , Linfoma/complicações , Linfoma/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Sensibilidade e EspecificidadeRESUMO
In Japan, we encountered a pandemic expansion of novel influenza A(H1N1) in September 2009, but the impact on patients with underlying disease remained unclear. The Tokyo Children Cancer Study Group (TCCSG) established a "novel influenza information-sharing system" to share real time information on how the novel influenza affects pediatric patients with cancer or other hematologic disorders. To facilitate reporting, we limited the items to only the basic data (underlying disease, age, sex), influenza-associated data (diagnostic method, therapy and outcome) and allowed space for free comments. We could share the information promptly, and found that this system worked well. One hundred and fifteen patients were reported between September 2009 and February 2010. Although eight patients needed to be hospitalized, none of the patients died, were admitted to intensive care units or demonstrated sequelae. The novel influenza A(H1N1) did not have a strong impact on pediatric patients with cancer or hematologic disorder at least during the 2009-2010 season.
Assuntos
Redes de Comunicação de Computadores , Doenças Hematológicas , Hospedeiro Imunocomprometido , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Sistemas de Informação , Neoplasias , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Influenza Humana/diagnóstico , Influenza Humana/epidemiologia , Japão/epidemiologia , Masculino , Risco , Fatores Sexuais , Fatores de TempoRESUMO
BACKGROUND: Definitive diagnosis is crucial in reducing morbidity and mortality from pandemic influenza A H1N1 2009 (A/H1N1/2009), especially in high-risk populations. We recently developed a rapid diagnosis kit (RDK) capable of specifically detecting A/H1N1/2009. OBJECTIVES: To evaluate the diagnostic capability of the RDK in a multicenter, prospective trial. STUDY DESIGN: Samples were obtained by nasal swab from patients with suspected influenza. The diagnostic capability of the RDK was compared with that of the standard, real-time reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS: Of 266 patients who met the criteria, 122 and 92 were positive for A/H1N1/2009 influenza by PCR and by the newly developed RDK, respectively. The sensitivity, specificity and positive and negative predictive values of the RDK were 73.0%, 97.9%, 96.7% and 81.0%, respectively. A/H1N1/2009 detection rates by the RDK were significantly lower in samples obtained from patients more than 3 days after onset than in samples obtained between 1 and 2 days. CONCLUSIONS: The A/H1N1/2009-specific RDK is a reliable test that can be used easily at a patient's bedside for rapid diagnosis of A/H1N1/2009. This test will be of key importance in the control of A/H1N1/2009.
Assuntos
Anticorpos Monoclonais/imunologia , Antígenos Virais/imunologia , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/diagnóstico , Kit de Reagentes para Diagnóstico/normas , Adolescente , Distribuição por Idade , Criança , Pré-Escolar , Cromatografia de Afinidade , Intervalos de Confiança , Feminino , Humanos , Lactente , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Influenza Humana/virologia , Japão , Masculino , Pandemias , Estudos Prospectivos , Kit de Reagentes para Diagnóstico/virologia , Sensibilidade e Especificidade , Distribuição por Sexo , Fatores de TempoRESUMO
Agranulocytosis is an extremely serious, although rare, adverse effect of antithyroid drugs (ATDs), including methimazole (MMI) and propylthiouracil (PTU), in children and adolescents. There are few reports about the characteristics of ATD-induced agranulocytosis in Japanese children and adolescents. This report presents the cases of three girls with ATD-induced agranulocytosis and a retrospective analysis of 18 patients with ATD-induced agranulocytosis, whose cases had been referred to the drug manufacturer, Chugai Pharmaceutical Co., Ltd. Our 3 patients, ranging in age from 12 to 14 yr, developed ATD-induced agranulocytosis between the 15th and 57th day of ATD treatment for hyperthyroidism. Fever and sore throat were the earliest symptoms of agranulocytosis. The patients were rescued by ceasing ATD therapy and administering antibiotics, potassium iodide, glucocorticoid, immunoglobulin and granulocyte colony-stimulating factor (G-CSF). We retrospectively analyzed 18 cases of ATD-induced agranulocytosis treated with MMI in 16 cases and PTU in 2 cases. Twelve patients were treated with 20-45 mg/d MMI. Agranulocytosis developed between the 15th and 1,344th day of therapy. In conclusion, considering the risk of ATD-induced agranulocytosis, we recommend low-dose MMI therapy for treatment of Graves' disease.
RESUMO
The MR imaging finding of a reversible splenial lesion with transiently reduced diffusion has been reported in patients with clinically mild encephalitis/encephalopathy, leading to a new clinical-radiological syndrome, clinically mild encephalitis/encephalopathy with a reversible splenial lesion. We recently experienced a 3-year-old boy with clinically mild encephalitis with a splenial lesion exhibiting transient reduced diffusion on admission. He recovered completely with no particular treatment within 2 weeks. Though the splenial lesion decreased in size, it was detected for over 5 months in T2-weighted imaging. It is suggested that a splenial lesion with transiently reduced diffusion in clinically mild encephalitis/encephalopathy is not always reversible, and could result in gliosis.
Assuntos
Corpo Caloso/patologia , Encefalite/diagnóstico , Pré-Escolar , Imagem de Difusão por Ressonância Magnética , Eletroencefalografia , Encefalite/patologia , Humanos , Masculino , Resultado do TratamentoRESUMO
Pseudohypoparathyroidism (PHP) is a metabolic disorder characterized by organ resistance to the action of parathyroid hormone. PHP type 1 is subclassified into two apparent disorders, type 1a (PHP1a) and type 1b (PHP1b). Patients with PHP1a show Albright hereditary osteodystrophy including short stature. Patients with PHP1b have no such skeletal defects, however, literature regarding the growth of PHP1b is not currently available. We evaluated growth charts of PHP patients, including four PHP1a patients and six PHP1b patients. Growth patterns were different between PHP type 1a and 1b. Adult height was abnormally low in all PHP1a patients. The growth pattern of PHP1a was characterized by mild growth impairment in the prepubertal period, a blunted growth spurt and premature cessation of the growth spurt. The adult height of male PHP1b was slightly lower than average. An early growth spurt was observed only in male patients with PHP1b and it may reduce the adult height of male patients with PHP1b. This warrants further investigation into the growth and pubertal development of PHP1b patients.