RESUMO
Spondylocarpotarsal synostosis syndrome (SCT) is a rare group of skeletal dysplasias, characterized by disproportionate short stature with a short trunk, abnormal segmentation of the spine with vertebral fusion, scoliosis and lordosis, carpal and tarsal synostosis, and mild facial dysmorphisms. While the majority of the cases show autosomal recessive inheritance, only a few cases of vertical transmissions, with MYH3 mutations, have been reported. Here we report a case with typical SCT, carrying a novel heterozygous mutation in MYH3. This observation supports the hypothesis of a pathogenic link between autosomal dominant SCT and heterozygous mutations in MYH3. Of note, our case showed basilar invagination on brain magnetic resonance imaging at the age of 10 years. Basilar invagination could be a rare complication of both autosomal recessive and dominant SCT, indicating that prompt investigation are warranted for SCT patients.
Assuntos
Anormalidades Múltiplas/genética , Proteínas do Citoesqueleto/genética , Heterozigoto , Vértebras Lombares/anormalidades , Doenças Musculoesqueléticas/genética , Escoliose/congênito , Sinostose/genética , Vértebras Torácicas/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Feminino , Humanos , Vértebras Lombares/patologia , Doenças Musculoesqueléticas/patologia , Escoliose/genética , Escoliose/patologia , Síndrome , Sinostose/patologia , Vértebras Torácicas/patologiaRESUMO
Germline or somatic gain-of-function mutations in the v-akt murine thymoma viral oncogene homolog 3 (AKT3) have been reported to cause syndromic megalencephaly. We describe a novel germline mutation, p.Glu40Lys, in AKT3. Phenotypically, the patient presented with megalencephaly with hypotonia, apparent connective tissue laxity, and growth hormone (GH) deficiency. To our knowledge, this is the first instance of a patient with megalencephaly with GH deficiency, harboring a germline de novo mutation in AKT3. © 2017 Wiley Periodicals, Inc.
Assuntos
Mutação em Linhagem Germinativa , Hormônio do Crescimento/deficiência , Megalencefalia/genética , Hipotonia Muscular/genética , Proteínas Proto-Oncogênicas c-akt/genética , Sequência de Aminoácidos , Povo Asiático , Sequência de Bases , Pré-Escolar , Tecido Conjuntivo/metabolismo , Tecido Conjuntivo/patologia , Exoma , Expressão Gênica , Hormônio do Crescimento/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Megalencefalia/diagnóstico , Megalencefalia/etnologia , Megalencefalia/patologia , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/etnologia , Hipotonia Muscular/patologia , Fenótipo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
There have been reports of the use of levothyroxine or levothyroxine plus liothyronine for consumptive hypothyroidism caused by hepatic hemangiomas. Administration of levothyroxine without liothyronine can be inadequate to maintain normal levels of both free T3 and free T4 in some patients. However, there is no report of treatment with liothyronine plus propranolol. We herein present a case in which we used liothyronine therapy for multifocal hepatic hemangiomas in a Japanese patient with low free T3 and normal free T4 levels. A 2-month-old Japanese male was referred to our hospital because of jaundice. Abdominal computed tomography showed multifocal hemangiomas in both lobes of the liver. TSH level was elevated, free T3 level was low, free T4 level was normal, and hypothyroidism due to hepatic hemangiomas was diagnosed. In addition to propranolol, liothyronine was started. We used liothyronine without levothyroxine for hypothyroidism because only free T3 level had decreased, whereas free T4 level remained in the normal range. The TSH and free T3 levels normalized in this patient in less than 1 month. The liothyronine dose was gradually reduced with regression of the hemangiomas, and liothyronine administration was discontinued at the age of 5 months. At the age of 11 months, growth and neurological development of the patient met age-specific norms, and he was euthyroid at that time. This is the first report demonstrating the use of liothyronine with propranolol for treatment of this type of consumptive hypothyroidism.
Assuntos
Hemangioma/fisiopatologia , Terapia de Reposição Hormonal , Hipotireoidismo/tratamento farmacológico , Neoplasias Hepáticas/fisiopatologia , Glândula Tireoide/efeitos dos fármacos , Tri-Iodotironina/uso terapêutico , Hemangioma/diagnóstico por imagem , Hemangioma/tratamento farmacológico , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/etiologia , Hipotireoidismo/fisiopatologia , Lactente , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Propranolol/uso terapêutico , Índice de Gravidade de Doença , Glândula Tireoide/fisiopatologia , Tiroxina/sangue , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Tri-Iodotironina/sangue , Ultrassonografia Doppler , Vasodilatadores/uso terapêuticoRESUMO
X-linked hypophosphatemia (XLH) is a group of rare disorders caused by defective proximal tubular reabsorption of phosphate. Mutations in the PHEX gene are responsible for the majority of cases. There are very few reports of long-term complications of XLH other than skeletal and dental diseases. The aim of this study was to identify the phenotypic presentation of XLH during adulthood including complications other than skeletal and dental diseases. The clinical and biochemical phenotype of 22 adult patients with a PHEX gene mutation were examined retrospectively from their medical records. 6 patients had hypertension. The average age of hypertension onset was 29.0 years. Secondary hyperparathyroidism preceded the development of hypertension in 5 patients. 1 patient developed tertiary hyperparathyroidism. 15 patients had nephrocalcinosis. 2 patients had chronic renal dysfunction. Patients with hypertension had a significantly lower eGFR (p=0.010) compared to patients without hypertension. No significant difference was found in any other parameters. To examine the genotype-phenotype correlation, 10 adult males were chosen for analysis. No significant genotype-phenotype correlation analysis was revealed in any of the complications. However, there was a possibility that the age at nephrocalcinosis onset was younger in the non-missense mutation group than in the missense mutation group (p=0.063). This study corroborated the view that early-onset hypertension could be one of the characteristic complications seen in XLH patients. Considering the limited number of our patients, further study is necessary to address a potential cause of hypertension. XLH patients require careful lifelong treatment.
Assuntos
Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Hiperparatireoidismo Secundário/etiologia , Hipertensão/etiologia , Nefrocalcinose/etiologia , Adolescente , Adulto , Idade de Início , Conservadores da Densidade Óssea/uso terapêutico , Criança , Pré-Escolar , Suplementos Nutricionais , Raquitismo Hipofosfatêmico Familiar/dietoterapia , Raquitismo Hipofosfatêmico Familiar/genética , Feminino , Hospitais Pediátricos , Humanos , Hidroxicolecalciferóis/uso terapêutico , Hiperparatireoidismo Secundário/epidemiologia , Hiperparatireoidismo Secundário/prevenção & controle , Hipertensão/epidemiologia , Hipertensão/prevenção & controle , Masculino , Prontuários Médicos , Mutação , Nefrocalcinose/epidemiologia , Nefrocalcinose/prevenção & controle , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Fosfatos/uso terapêutico , Prevalência , Estudos Retrospectivos , Tóquio/epidemiologia , Adulto JovemRESUMO
POU class 1 homeobox 1 (POU1F1) regulates pituitary cell-specific gene expression of somatotropes, lactotropes, and thyrotropes. In humans, two POU1F1 isoforms (long and short isoform), which are generated by the alternative use of the splice acceptor site for exon 2, have been identified. To date, more than 30 POU1F1 mutations in patients with combined pituitary hormone deficiency (CPHD) have been described. All POU1F1 variants reported to date affect both the short and long isoforms of the POU1F1 protein; therefore, it is unclear at present whether a decrease in the function of only one of these two isoforms is sufficient for disease onset in humans. Here, we described a sibling case of CPHD carrying a heterozygous mutation in intron 1 of POU1F1. In vitro experiments showed that this mutation resulted in exon 2-skipping of only in the short isoform of POU1F1, while the long isoform remained intact. This result strongly suggests the possibility, for the first time, that isolated mutations in the short isoform of POU1F1 could be sufficient for induction of POU1F1-related CPHD. This finding improves our understanding of the molecular mechanisms, and developmental course associated with mutations in POU1F1.
Assuntos
Hipopituitarismo/genética , Mutação de Sentido Incorreto , Fator de Transcrição Pit-1/genética , Criança , Análise Mutacional de DNA , Feminino , Células HeLa , Heterozigoto , Humanos , Íntrons/genética , LinhagemRESUMO
Mutations in DUOXA2, encoding dual oxidase maturation factor 2, is a rare genetic cause of congenital hypothyroidism. Only four biallelic DUOXA2 mutation carriers have been described to date. This study was conducted to report the clinical and genetic findings of a DUOXA2 mutation-carrying family, and to review the previously reported cases. The proband was a 4-year-old girl, who was diagnosed as having congenital hypothyroidism in the frame of newborn screening. She had a high serum TSH level (138 mU/L) and a low free T4 level (0.4 ng/dL). Ultrasonography revealed goiter. She was immediately treated with levothyroxine. At age 3 years, reevaluation of her thyroid function showed a slightly elevated serum TSH level (11.0 mU/L) with normal free T4 level. Screening of the eleven congenital hypothyroidism-related genes demonstrated a previously reported nonsense DUOXA2 mutation (p.Tyr138*) in the homozygous state. Unexpectedly, we also found that the elder brother of the proband, who had no significant past medical history, had the identical homozygous mutation. Using expression experiments with HEK293 cells, we confirmed that p.Tyr138* was a loss-of-function mutation. In the literature, clinical courses of three patients were described, showing characteristic age-dependent improvement of the thyroid function. In conclusion, The proband showed comparable clinical phenotype to previously reported cases, while her brother was unaffected. The phenotypic spectrum of DUOXA2 mutations could be broader than currently accepted.
Assuntos
Hipotireoidismo Congênito/genética , Proteínas de Membrana/genética , Glândula Tireoide/diagnóstico por imagem , Tireotropina/sangue , Tiroxina/uso terapêutico , Pré-Escolar , Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/tratamento farmacológico , Feminino , Células HEK293 , Homozigoto , Humanos , Recém-Nascido , Masculino , Mutação , Triagem Neonatal , Irmãos , Tiroxina/sangue , Resultado do Tratamento , UltrassonografiaRESUMO
Heterozygous and/or homozygous HESX1 mutations have been reported to cause isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD), in association with septo optic dysplasia (SOD). We report a novel heterozygous HESX1 mutation in a CPHD patient without SOD phenotypes. The propositus was a one-year-old Japanese girl. Shortly after birth, she was found to be hypoglycemic. She was diagnosed with central adrenal insufficiency based on low cortisol and ACTH at a time of severe hypoglycemia. Further endocrine studies indicated that the patient also had central hypothyroidism and growth hormone deficiency. Using a next-generation sequencing strategy, we identified a novel heterozygous HESX1 mutation, c.326G>A (p.Arg109Gln). Western blotting and subcellular localization revealed no significant difference between wild type and mutant HESX1. Electrophoretic mobility shift assays showed that the mutant HESX1 abrogated DNA-binding ability. Mutant HESX1 was unable to repress PROP1-mediated activation. In conclusion, this study identified Arg109 as a critical residue in the HESX1 protein and extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in HESX1. When multiple genes need to be analyzed for mutations simultaneously, targeted sequence analysis of interesting genomic regions is an attractive approach.
Assuntos
Proteínas de Homeodomínio/genética , Hipopituitarismo/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Feminino , Proteínas de Homeodomínio/química , Humanos , Lactente , Japão , Fenótipo , Displasia Septo-Óptica/genéticaRESUMO
BACKGROUND: A radiologic diagnosis of hypochondroplasia is hampered by the absence of age-dependent radiologic criteria, particularly in the neonatal period. OBJECTIVE: To establish radiologic criteria and scoring system for identifying neonates with fibroblast growth factor receptor 3 (FGFR3)-associated hypochondroplasia. MATERIALS AND METHODS: This retrospective study included 7 hypochondroplastic neonates and 30 controls. All subjects underwent radiologic examination within 28 days after birth. We evaluated parameters reflecting the presence of (1) short ilia, (2) squared ilia, (3) short greater sciatic notch, (4) horizontal acetabula, (5) short femora, (6) broad femora, (7) metaphyseal flaring, (8) lumbosacral interpedicular distance narrowing and (9) ovoid radiolucency of the proximal femora. RESULTS: Only parameters 1, 3, 4, 5 and 6 were statistically different between the two groups. Parameters 3, 5 and 6 did not overlap between the groups, while parameters 1 and 4 did. Based on these results, we propose a scoring system for hypochondroplasia. Two major criteria (parameters 3 and 6) were assigned scores of 2, whereas 4 minor criteria (parameters 1, 4, 5 and 9) were assigned scores of 1. All neonates with hypochondroplasia in our material scored ≥6. CONCLUSION: Our set of diagnostic radiologic criteria might be useful for early identification of hypochondroplastic neonates.
Assuntos
Pontos de Referência Anatômicos/diagnóstico por imagem , Osso e Ossos/anormalidades , Nanismo/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico , Lordose/diagnóstico , Radiografia Abdominal/normas , Radiografia Torácica/normas , Radiologia/normas , Nanismo/genética , Feminino , Fêmur/anormalidades , Fêmur/diagnóstico por imagem , Humanos , Recém-Nascido , Japão , Deformidades Congênitas dos Membros/genética , Lordose/genética , Masculino , Mutação/genética , Neonatologia/normas , Ossos Pélvicos/anormalidades , Ossos Pélvicos/diagnóstico por imagem , Guias de Prática Clínica como Assunto , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Coluna Vertebral/anormalidades , Coluna Vertebral/diagnóstico por imagemRESUMO
Most cases of osteogenesis imperfecta (OI) are caused by heterozygous mutations in COL1A1 or COL1A2, the genes encoding the two type I procollagen alpha chains, proα1 (I) and proα2 (I). We report on a unique case of severe OI, a long term survivor of lethal type II OI, rather than progressively deforming type III, due to double substitutions of glycine residues in COL1A2 (p.Gly208Glu and p.Gly235Asp), located on the same allele. To the best of our knowledge, this is the first example of a patient with double COL1A2 glycine substitution mutations on the same allele. We show for the first time that double COL1A2 glycine substitution mutations located near the amino-terminal triple helical region, which individually are likely to result in mild OI, cause severe OI in combination.
Assuntos
Substituição de Aminoácidos/genética , Colágeno Tipo I/genética , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/genética , Sequência de Bases , Análise Mutacional de DNA , Feminino , Glicina , Humanos , Lactente , Recém-Nascido , Japão , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Multiplex , RadiografiaRESUMO
Sotos syndrome (SoS, OMIM #117550) is an overgrowth syndrome. Deletions or intragenic mutations of the NSD1 , which is located at chromosome 5q35, are responsible for more than 75% of SoS. Conventionally, neonatal hypoglycemia was reported briefly as one of the infrequent symptoms of SoS. However, Matsuo et al. published a report describing five patients with SoS who presented with transient hyperinsulinemic hypoglycemia (HIH) in the neonatal period. We report on an additional patient of SoS, who presented transient HIH in the neonatal period. All of this patient and previous patients have microdeletions at the 5q35 chromosome. Therefore, we examined the following three in considering the possibility that other factor than NSD1 caused HIH. 1) This patient had no mutation of four currently known HIH related genes, ABCC8, KCNJ11, GLUD1, and GCK. 2) He had no further deletion than commonly observed region encompassing NSD1 by comparative genomic hybridization to DNA microarrays. 3) He had no mutation in the 5q35 region in the non-deleted chromosome using exsome sequence analysis. In conclusion, our patient supported that HIH could be one of the characteristic symptoms of SoS in the neonatal period, and could be useful for early diagnosis.
Assuntos
Hiperinsulinismo Congênito/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Síndrome de Sotos/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Hibridização Genômica Comparativa , Hiperinsulinismo Congênito/complicações , Hiperinsulinismo Congênito/fisiopatologia , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Humanos , Masculino , Mutação , Síndrome de Sotos/complicações , Síndrome de Sotos/fisiopatologiaRESUMO
The common phenotype of nuclear receptor superfamily 5, group A, member 1 (NR5A1) gene mutations in 46,XY is gonadal dysgenesis without adrenal deficiency. Though the phenotype of gonadal dysgenesis is variable, ranging from complete female to normal male genitalia, an asymptomatic 46,XY male is rare. Preserved fertility has so far been described in only three affected 46,XY males with different mutations, but no functional analysis of these mutations has been performed. Here, we report on male siblings with hypospadias and their asymptomatic father in whom we identified a heterozygous NR5A1 mutation of c.910G>A, p.E304K. Western blotting and subcellular localization revealed no significant difference between the wild type (WT) and E304K. Electrophoretic mobility shift assay experiments showed that E304K abrogated DNA-binding ability. E304K reduced transactivation and had no dominant negative effect. In conclusion, we report on a novel hypomorphic NR5A1 mutation, which may be associated with the phenotype of the family.
Assuntos
Fertilidade/genética , Hipospadia/genética , Mutação , Fator Esteroidogênico 1/genética , Adolescente , Humanos , MasculinoRESUMO
We report a 4-year-old boy with sclerosteosis associated with severe digital dysostosis. The initial medical consultation was prompted by bilateral, asymmetrical syndactyly of the index and middle fingers. The left index finger had complicated phalangeal anomalies: hyperphalangy (supernumerary phalanx distal to the middle phalanx) and hypoplasia with bracket epiphyses of the proximal and middle phalanges. Development of facial nerve palsy, hearing impairment and generalized osteosclerosis had occurred between 3 years and 4 years of age, with the subsequent identification of a homozygous SOST mutation. Bilateral second and third fingers syndactyly associated with abnormal patterning of the same fingers should be considered prodromal signs of sclerosteosis.
Assuntos
Dedos/anormalidades , Dedos/diagnóstico por imagem , Deformidades Congênitas da Mão/diagnóstico por imagem , Hiperostose/diagnóstico por imagem , Sindactilia/diagnóstico por imagem , Pré-Escolar , Deformidades Congênitas da Mão/complicações , Humanos , Hiperostose/complicações , Masculino , Radiografia , Sindactilia/complicaçõesRESUMO
UNLABELLED: Caffey disease, also known as infantile cortical hyperostosis, is a rare bone disease characterized by acute inflammation with swelling of soft tissues and hyperostosis of the outer cortical surface in early infancy. The common heterozygous mutation of the COL1A1 gene, p.Arg1014Cys, has been reported in patients with Caffey disease. However, its pathogenesis remains to be elucidated, and the reason for the incomplete penetrance and transient course of the disease is still unclear. In the present study, we performed mutation analysis of the COL1A1 and COL1A2 genes and measured bone mineral density in two Japanese familial cases of Caffey disease. The index case and two clinically healthy members of one family carry the common heterozygous mutation; in contrast, no mutation in COL1A1 or COL1A2 was identified in the affected members of the second family. In addition, we found normal bone mineral density in adult patients of both families who have had an episode of cortical hyperostosis regardless of the presence or absence of the common p.Arg1014Cys mutation. CONCLUSION: The results reveal that Caffey disease is genetically heterogeneous and that affected and unaffected adult patients with or without the common COL1A1 mutation have normal bone mineral density.
Assuntos
Densidade Óssea/fisiologia , Colágeno Tipo I/genética , Hiperostose Cortical Congênita/genética , Mutação , Absorciometria de Fóton , Povo Asiático , Osso e Ossos/diagnóstico por imagem , Pré-Escolar , Cadeia alfa 1 do Colágeno Tipo I , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Masculino , LinhagemRESUMO
INTRODUCTION: Both duplications encompassing SOX3 and loss-of function mutations in SOX3 have been reported in a minor portion of X-linked isolated growth hormone deficiency (GHD) or combined pituitary hormone deficiency (CPHD) patients with or without mental retardation. PATIENTS AND METHODS: We report a Japanese male patient with molecularly confirmed Kabuki syndrome who was found to have CPHD. We analyzed all coding exons and flanking introns of currently known nine genes responsible for CPHD by PCR-based sequencing. RESULTS: In this CPHD patient, we identified a novel hemizygous 21-base pair deletion, resulting in the loss of 7 alanine residues from polyalanine (PA) tracts of SOX3. The clinically and endocrinologically normal mother of the patient carried the same deletion in a heterozygous manner. In vitro experiments showed that the del 7A SOX3 had increased transactivation of the HESX1 promoter. CONCLUSION: Our study provides additional evidence that deletion in PA tracts of SOX3 is associated with hypopituitarism. Female carriers of SOX3 PA tract deletions will show a broad phenotypic spectrum, ranging from clinically normal to CPHD.
Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/genética , Hipopituitarismo/genética , Proteínas de Neoplasias/genética , Fatores de Transcrição SOXB1/genética , Doenças Vestibulares/genética , Animais , Células COS , Criança , Pré-Escolar , Chlorocebus aethiops , Análise Mutacional de DNA , Feminino , Humanos , Hipopituitarismo/patologia , Hipopituitarismo/fisiopatologia , Lactente , Masculino , Mutação/genética , Linhagem , Inativação do Cromossomo X/genéticaAssuntos
Conservadores da Densidade Óssea/administração & dosagem , Difosfonatos/administração & dosagem , Doenças do Prematuro/tratamento farmacológico , Recém-Nascido de muito Baixo Peso , Osteogênese Imperfeita/tratamento farmacológico , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Esquema de Medicação , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/diagnóstico , Infusões Intravenosas , Masculino , Osteogênese Imperfeita/diagnóstico , PamidronatoRESUMO
Hypochondroplasia (HCH) is the mildest phenotype among fibroblast growth factor receptor 3 (FGFR3)-associated skeletal dysplasias. Affected individuals usually presents with mild short stature in preschool age. It was uncommon that a diagnosis of HCH is made in young affected children. Recently, however, prenatal ultrasound (US) has increased likelihood of detecting in utero mild short limbs. There have been a few reports on the early diagnosis of HCH in the neonatal period preceded by a suspicion of skeletal dysplasia on fetal US. However, the proper diagnosis of HCH is hampered by absence of the radiological criteria relevant to age, particularly those in the neonatal period. We report on the clinical and radiological findings in two HCH children with a FGFR3 mutation. In both children, fetal US showed short femora and relatively increased biparietal diameter (BPD). However, postnatal assessment failed to make a specific diagnosis in the neonatal period. The correct diagnosis of HCH was accomplished by reassessment after exacerbation of postnatal short stature. In retrospective radiological review, the radiological findings relevant to HCH were discernible more easily in the neonatal period than at age of 3 years.
Assuntos
Osteocondrodisplasias/diagnóstico por imagem , Pré-Escolar , Humanos , Recém-Nascido , Funções Verossimilhança , Masculino , Mutação , Osteocondrodisplasias/genética , Radiografia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Ultrassonografia Pré-NatalRESUMO
Rabson-Mendenhall syndrome (RMS) is a genetic disorder characterized by severe insulin resistance and somatic characteristics. Recombinant insulin-like growth factor 1 (r-IGF-1) is used to treat RMS, as the IGF-1 and insulin receptors share homology. However, the effect of r-IGF-1 varies in patients and it is difficult to manage metabolic status appropriately in r-IGF-1 resistant cases. We report a Japanese boy with RMS who showed resistance to r-IGF-1 therapy and a novel mutation in the insulin receptor in the tyrosine kinase domain. Mutations in this region disturb tyrosine kinase catalytic activity in IGF-1 receptors as a result of dominant negative effects. We consider this mutation to be the cause of resistance to r-IGF-1. The patient also exhibited radiographical features of medullary sponge kidney and had severe nephrocalcinosis and hypokalemia, indicating Bartter syndrome. However, analysis revealed no mutations in the responsible genes and the etiology of the renal abnormalities therefore remains unknown.