RESUMO
CONTEXT: Adrenal crisis (AC) is a life-threatening complication that occurs during follow-up of patients with adrenal insufficiency (AI). No prospective study has thoroughly investigated AC in children with primary and secondary AI. OBJECTIVE: This work aimed to determine the incidence and risk factors for AC in patients with pediatric-onset AI. METHODS: This multicenter, prospective cohort study conducted in Japan enrolled patients diagnosed with AI at age ≤15 years. The incidence of AC was calculated as events per person-year (PY), and risk factors for AC were assessed using Poisson regression multivariable analysis. RESULTS: The study population comprised 349 patients (164 male, 185 female) with a total follow-up of 961 PY. The median age at enrollment was 14.3 years (interquartile range [IQR] 8.5-21.2 years), and the median follow-up was 2.8 years (IQR 2.2-3.3 years). Of these patients, 213 (61%) had primary AI and 136 (39%) had secondary AI. Forty-one AC events occurred in 31 patients during the study period. The calculated incidence of AC was 4.27 per 100 PY (95% CI, 3.15-5.75). Poisson regression analysis identified younger age at enrollment (relative risk [RR] 0.93; 95% CI, 0.89-0.97) and increased number of infections (RR 1.17; 95% CI, 1.07-1.27) as significant risk factors. Female sex (RR 0.99; 95% CI, 0.53-1.86), primary AI (RR 0.65; 95% CI, 0.30-1.41), or equivalent dosage of hydrocortisone per square meter of body area (RR 1.02; 95% CI, 0.96-1.08) was not a significant risk factor. CONCLUSION: A substantial proportion of patients with pediatric-onset AI experience AC. Younger age and an increased number of infections are independent risk factors for developing AC in these patients.
Assuntos
Insuficiência Adrenal , Humanos , Masculino , Feminino , Insuficiência Adrenal/epidemiologia , Insuficiência Adrenal/etiologia , Incidência , Criança , Fatores de Risco , Adolescente , Estudos Prospectivos , Japão/epidemiologia , Adulto Jovem , Pré-Escolar , Seguimentos , Idade de Início , HidrocortisonaRESUMO
5α-reductase type 2 (5αRD2) deficiency is a 46,XY disorder of sex development caused by impaired conversion of testosterone (T) to dihydrotestosterone (DHT). Penile enlargement therapy is important for male patients with 46,XY 5αRD2 deficiency who have undermasculinized external genitalia, such as severe micropenis. High-dose T and percutaneous DHT replacement are reportedly efficacious for penile enlargement in patients with this disorder. We presented herein the longitudinal course of four patients with 46,XY 5αRD2 deficiency who received T and DHT. T replacement therapy during infancy increased the stretched penile length (SPL) in three of the patients but was ineffective in one patient. DHT was administered to the three patients after T replacement therapy and further increased the SPL. During and after puberty, two patients asked for and received T replacement therapy, which contributed to increasing their SPL. A semen test in one patient with T replacement therapy at age 27 years revealed cryptozoospermia despite normal testicular volume. The clinical course of our patients during infancy indicated that DHT therapy may be preferrable to T replacement therapy for penile enlargement in patients with 5αRD2 deficiency. During and after puberty, T replacement therapy promoted penile enlargement possibly because of increased conversion of T to DHT via increased 5α-reductase type 1 activity even in patients in whom it was ineffective during infancy. In conclusion, DHT is effective for penile enlargement during infancy in patients with 5αRD2 deficiency while T replacement therapy is a viable option during puberty.
Assuntos
Di-Hidrotestosterona , Testosterona , Humanos , Masculino , Lactente , Adulto , Testosterona/uso terapêutico , Di-Hidrotestosterona/uso terapêutico , Puberdade , Oxirredutases , Progressão da DoençaRESUMO
Isolated growth hormone deficiency type II (IGHD2) is mainly caused by heterozygous splice-site mutations in intron 3 of the GH1 gene. A dominant-negative effect of the mutant GH lacking exon 3 on wild-type GH secretion has been proposed; however, the molecular mechanisms involved are elusive. To uncover the molecular systems underlying GH deficiency in IGHD2, we established IGHD2 model mice, which carry both wild-type and mutant copies of the human GH1 gene, replacing each of the endogenous mouse Gh loci. Our IGHD2 model mice exhibited growth retardation along with intact cellular architecture and mildly activated endoplasmic reticulum stress in the pituitary gland, caused by decreased GH-releasing hormone receptor (Ghrhr) and Gh gene promoter activities. Decreased Ghrhr and Gh promoter activities were likely caused by reduced levels of nuclear CREB3L2, which was demonstrated to stimulate Ghrhr and Gh promoter activity. To our knowledge, this is the first in vivo study to reveal a novel molecular mechanism of GH deficiency in IGHD2, representing a new paradigm that differs from widely accepted models.
Assuntos
Nanismo Hipofisário/etiologia , Hormônio do Crescimento/metabolismo , Receptores de Neuropeptídeos/metabolismo , Receptores de Hormônios Reguladores de Hormônio Hipofisário/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Nanismo Hipofisário/patologia , Feminino , Hormônio do Crescimento/genética , Humanos , Masculino , Camundongos , Hipófise/metabolismo , Hipófise/ultraestrutura , Regiões Promotoras Genéticas , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genéticaRESUMO
The endoplasmic reticulum (ER) is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the "unfolded protein response" (UPR), which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI), Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2) are discussed in this article.
Assuntos
Doenças do Sistema Endócrino/etiologia , Doenças do Sistema Endócrino/metabolismo , Estresse do Retículo Endoplasmático , Animais , Modelos Animais de Doenças , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/terapia , Humanos , Mamíferos , Transdução de Sinais , Resposta a Proteínas não DobradasRESUMO
Estrogen replacement therapy in Turner syndrome should theoretically mimic the physiology of healthy girls. The objective of this study was to describe final height and bone mineral density (BMD) in a group of 17 Turner syndrome patients (group E) who started their ethinyl estradiol therapy with an ultra-low dosage (1-5 ng/kg/day) from 9.8-13.7 years. The subjects in group E had been treated with GH 0.35 mg/kg/week since the average age of 7.4 years. The 30 subjects in group L, one of the historical groups, were given comparable doses of GH, and conjugated estrogen 0.3125 mg/week â¼0.3125 mg/day was initiated at 12.2-18.7 years. The subjects in group S, the other historical group, were 21 patients who experienced breast development and menarche spontaneously. Final height (height gain < 2 cm/year) in group E was 152.4 ± 3.4 cm and the standard deviation (SD) was 2.02 ± 0.62 for Turner syndrome. The final height in group L was 148.5 ± 3.0 cm with a SD of 1.30 ± 0.55, which was significantly different from the values for group E. The volumetric BMD of group S (0.290 ± 0.026 g/cm3) was significantly different from that of group L or E (0.262 or 0.262 g/cm3 as a mean, respectively). This is the first study of patients with Turner syndrome where estrogen was administered initially in an ultra-low dose and then increased gradually. Our estrogen therapy in group E produced good final height but not ideal BMD.
Assuntos
Estatura/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Terapia de Reposição de Estrogênios/métodos , Etinilestradiol/administração & dosagem , Síndrome de Turner/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Relação Dose-Resposta a Droga , Etinilestradiol/efeitos adversos , Feminino , Seguimentos , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Lactente , Japão , Menarca/efeitos dos fármacosRESUMO
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was originally reported as a responsible gene for generalized arterial calcification in infancy (GACI). Though the prognosis of GACI patients is poor because of myocardial infarction and heart failure in relation to medial calcification of the coronary arteries, some patients rescued by bisphosphonate treatment have been reported. Recently, ENPP1 is also reported as responsible for autosomal recessive hypophosphatemic rickets type 2. We show here a boy with homozygous ENPP1 mutations diagnosed as having GACI in early infancy. After the diagnosis, he was treated with etidronate disodium (EHDP) in combination with antihypertensive drugs. The calcification of major arteries was diminished and disappeared by the age of eight months. He also showed mild hypophosphatemia (2.6-3.7 mg/dl) from the age of one year. After the treatment with EHDP for five years, he showed genu valgum with hypophosphatemia (2.6 mg/dl). He was diagnosed as having hypophosphatemic rickets at the age of seven years. The findings that hyper-mineralization of the arteries and hypo-mineralization of the bone observed in the same patient are noteworthy. ENPP1 could be regarded as a controller of the calcification of the whole body at least in part.
RESUMO
Dominantly inherited isolated GH deficiency is mainly caused by a heterozygous donor site mutation of intron 3 in the GH1 gene. An exon 3 deletion in GH (del32-71 GH) is produced from a mutant allele, whereas wild-type GH is produced from the other allele. Several studies have demonstrated a dominant negative effect of del32-71 GH on wild-type GH secretion, but the precise molecular mechanisms remain unclear. We hypothesized that unfolded del32-71 GH accumulates in the endoplasmic reticulum (ER) and causes ER stress and apoptosis in somatotrophs, promoting GH deficiency. To evaluate del32-71 GH-mediated ER stress, we established GH4C1 cell lines with doxycycline (dox)-controlled del32-71 GH expression. In 20 of 23 dox-controlled cell lines, the concentration of wild-type GH in the culture medium significantly decreased with del32-71 GH induction, demonstrating the dominant negative effect of this mutant. Cell viability, mRNA abundance of ER stress-response genes, caspase activation, and DNA fragmentation were evaluated in 5 dox-controlled cell lines selected as cellular models. In 4 of the 5 cell lines, del32-71 GH induction decreased cell viability, increased expression of 3 major ER stress response pathways (PRKR-like endoplasmic reticulum kinase [PERK], activating transcription factor-6 [ATF6], and inositol requirement 1 [IRE1]), and induced caspase-3 and caspase-7 activation. In 1 of the 4 cell lines, DNA fragmentation was demonstrated. Finally, overexpression of XBP1(S), a nuclear transcription factor downstream of IRE1, completely reversed the observed caspase activation. These data suggested that del32-71 GH-mediated ER stress and apoptosis contributed to the decrease in wild-type GH secretion observed in GH deficiency due to the GH1 gene slice-site mutations.
Assuntos
Apoptose , Nanismo Hipofisário/genética , Estresse do Retículo Endoplasmático , Hormônio do Crescimento Humano/genética , Mutação , Sítios de Splice de RNA , Somatotrofos/metabolismo , Alelos , Animais , Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Doxiciclina/farmacologia , Nanismo Hipofisário/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Deleção de Genes , Hormônio do Crescimento Humano/metabolismo , Humanos , Regiões Promotoras Genéticas/efeitos dos fármacos , Ratos , Proteínas Recombinantes/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Somatotrofos/efeitos dos fármacos , Somatotrofos/ultraestrutura , Regulação para Cima/efeitos dos fármacosRESUMO
The combination of holoprosencephaly and ectrodactyly, also known as Hartsfield syndrome, represents a unique genetic entity. An X-linked recessive mode of transmission has been suggested for this condition based on the observation that male patients have preferentially been affected. Thus far, no candidate genes have been suggested on the X chromosome. We report a male patient with a full-blown Hartsfield syndrome phenotype who had microduplication at Xq24 involving four genes. He presented with bilateral ectrodactyly of the hands (both hands had four fingers with a deep gap between the 2nd and 3rd digits), cleft lip and palate, and a depressed nasal bridge. Magnetic resonance imaging of the brain revealed lobar holoprosencephaly. His G-banded karyotype was normal. Array comparative genomic hybridization (CGH) using the Agilent 244K Whole Human Genome CGH array revealed a microduplication at Xq24 of 210 kb. Parental testing revealed that the deletion was derived from the asymptomatic mother. Of the genes on the duplicated interval, the duplications of SLC25A43 and SLC25A5 appeared to be the most likely to explain the patient's phenotype. From a clinical standpoint, it is important to point out that the propositus, who performs relatively well with holoprosencephaly and has a developmental quotient around 70, has survived multiple life-threatening episodes of hypernatremia. Awareness of the risk of hypernatremia is of great importance for the anticipatory management of patients with ectrodactyly and an oral cleft, even in the absence of overt hypotelorism.
Assuntos
Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Duplicação Cromossômica , Cromossomos Humanos X/genética , Fenda Labial/genética , Fenda Labial/patologia , Fissura Palatina/genética , Fissura Palatina/patologia , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Holoprosencefalia/genética , Holoprosencefalia/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Criança , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Dedos/anormalidades , Dedos/patologia , Humanos , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Imageamento por Ressonância Magnética , MasculinoRESUMO
X-linked hypophosphatemic rickets (XLH) is caused by inactivating mutations in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene. Deletion of Phex leads to increased serum fibroblast growth factor23 (FGF23) levels in mouse. The aim is to assure the clinical usefulness of FGF23 determination in the diagnosis of XLH. Participants were 21 patients with XLH having abnormalities in PHEX from 13 kindred (PtPHEX: 1 to 42 years old; 10 males, 11 females) and 55 healthy controls (1 month to 18 years old; 27 males, 28 females). Temporal changes in FGF23 were determined by a single oral phosphate administration in PtPHEX and an ad lib diet in controls. Reference ranges of intact FGF23 (iFGF23) for children were determined. iFGF23 level which distinguish between controls and PtPHEX were validated. Correlations between iFGF23 and the severity of XLH (gender, age of onset, bone deformity, The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmPO(4)/GFR), inorganic phosphate (IP), Alkaline Phosphatase (ALP), therapeutic dose) were investigated. Increasing tendency after phosphate administration and no general tendency after breakfast in iFGF23 were observed. Reference range (5(th) and 95(th) percentiles) of iFGF23 for children (12.9 and 51.2 pg/mL) was similar to that for adults. iFGF23 were above the reference range in 19 of 21 PtPHEX (40 to 4710 pg/mL). iFGF23 did not correlate with any index of severity of XLH. Relatively high iFGF23 despite hypophosphatemia is one of the clinical indicators to diagnose XLH.
Assuntos
Raquitismo Hipofosfatêmico Familiar/diagnóstico , Fatores de Crescimento de Fibroblastos/sangue , Doenças Genéticas Ligadas ao Cromossomo X , Hipofosfatemia/sangue , Adolescente , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Diagnóstico Diferencial , Raquitismo Hipofosfatêmico Familiar/sangue , Raquitismo Hipofosfatêmico Familiar/genética , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/fisiologia , Humanos , Hipofosfatemia/diagnóstico , Hipofosfatemia/genética , Lactente , Masculino , Concentração Osmolar , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Prognóstico , Adulto JovemRESUMO
We report the cases of 3 children with plastic bronchitis associated with 2009 H1N1 influenza virus infection. These 3 children shared common clinical and radiologic features: rapid and progressive respiratory distress with whole lung atelectasis on chest radiograph. In children with severe respiratory symptoms accompanied by H1N1 influenza, plastic bronchitis should be considered.
Assuntos
Bronquite/virologia , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/virologia , Bronquite/diagnóstico , Bronquite/patologia , Criança , Pré-Escolar , Feminino , Humanos , Influenza Humana/diagnóstico , Masculino , Atelectasia Pulmonar/virologia , Radiografia TorácicaRESUMO
The gonadal function of patients with Turner syndrome (TS) is variable. Individuals with mosaicism characterized by 45,X/46,XX or 45,X/47,XXX are more likely to experience spontaneous menarche compared with other karyotypes. Prepubertal gonadotropins of TS patients with spontaneous menarche are reportedly normal or significantly lower than those of patients with induced menarche. The present study investigated an index of spontaneous and cyclical menstruation at 10-12 years old in TS. Subjects comprised 50 patients with TS, divided into three groups: Group A (n=7), with spontaneous menarche before 16 years old and regular menstruation for at least 1 year and 6 months; Group B (n=6), with irregular menstruation since menarche leading to secondary amenorrhea despite spontaneous menarche before 16 years old; and Group C (n=37), without spontaneous breast budding before 14 years old or without spontaneous menarche before 16 years old. Karyotype, LH and FSH concentrations at 10 and 12 years old were analyzed retrospectively. Spontaneous and cyclical menstruation was more frequently observed in TS with mosaicism characterized by 45,X/46,XX or 45,X/47,XXX than in TS with other karyotypes, as previously described. Spontaneous and cyclical menstruation in TS was observed when serum FSH level was <10 mIU/mL at 12 years old, suggesting this FSH level as an index of spontaneous and cyclical menstruation in TS.
Assuntos
Hormônio Foliculoestimulante Humano/sangue , Ciclo Menstrual , Síndrome de Turner/sangue , Síndrome de Turner/fisiopatologia , Adolescente , Adulto , Amenorreia/etiologia , Biomarcadores/sangue , Cromossomos Humanos X/genética , Feminino , Humanos , Cariotipagem , Estudos Longitudinais , Hormônio Luteinizante/sangue , Prontuários Médicos , Menarca , Mosaicismo , Puberdade/sangue , Síndrome de Turner/genética , Adulto JovemRESUMO
The treatment for hypophosphatemic rickets in children includes phosphate and vitamin D preparations. In children, this regimen significantly improves symptoms, while a treatment for adult patients has not been established. We therefore investigated the clinical courses of 15 adult patients who discontinued therapy when final height was achieved in order to assess the necessity of treatment in adulthood. Thirteen patients developed symptomatic complications, including bone fractures. Among the 13, the 10 patients who restarted therapy all showed clinical improvement, and no side effects of treatment were observed. This study shows that there are some patients with hypophosphatemic osteomalacia who need continuous treatment during adulthood.
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Auxological data are the gold standard indexes of the therapeutic conditions in patients with CYP21 deficiency over long-term periods, whereas urinary pregnanetriol (PT) for 24 h has been used as an index for short-term periods. We previously reported that the range of 1.2-2.1 mg/m(2)/day of PT for 24 h (24-h PT) could be used as an index of optimal control in patients with CYP21 deficiency. The purpose of this study was to analyze the range of PT in the first morning urine samples (morning PT) as an index of optimal control in patients with CYP21 deficiency. First, the therapeutic periods of 15 participants (aged 2 yr and 5 mo to 17 yr and 4 mo) were classified into excessive, good or poor control periods using auxological data and Cushing-like symptoms, and 24-h PT levels were analyzed in each period, retrospectively. The 95% confidence intervals for the means of 24-h PT levels in the excessive, good and poor control periods were 0.24-2.24 (n=25), 2.88-4.92 (n=114) and 13.26-21.28 (n=72) mg/gCr, respectively. Subsequently, 24-h PT and morning PT levels collected on the same day were analyzed for 14 participants (aged 9 mo to 29 yr and 8 mo). There was a significant correlation between the above two PT levels (n=25, p<0.0001). When the 24-h PT range of the good control period, 2.88-4.92 mg/gCr, was adjusted by the correlation, the ideal morning PT range became 2.15-3.34 mg/gCr. In conclusion, a morning PT in the range of 2.2-3.3 mg/gCr can be used as an index of optimal control in patients with CYP21 deficiency.
RESUMO
Auxological data is the gold standard index of the therapeutic condition in CYP21A2 deficiency over a long-range period, whereas urinary pregnanetriol for 24 h (PT) is variable for a shorter-range period. Ideal PT levels in comparison with auxological data have not been reported. The main purpose of this study was to analyze ideal PT values as an index of optimal control for CYP21A2 deficiency. First, inter-daily fluctuation of PT was analyzed in one participant. PT levels were distributed over a wide range of 0.44-14.7 mg/day (n=42) in this participant, suggesting that the therapeutic condition should be judged by multiple PT samples. Second, the therapeutic periods of 15 participants with CYP21A2 deficiency were classified using auxological data and Cushing-like symptoms, and the PT levels were analyzed in each period retrospectively. The 95% confidence intervals for the means of the PT levels in the excessive, good and poor control periods were 0.03-1.25 (n=26), 1.23-2.09 (n=116), and 5.35-8.37 (n=72) mg/m(2)/day, respectively. In conclusion, 1.2-2.1 mg/m(2)/day of PT values can be used as an index of optimal control in CYP21A2 deficiency.
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The Wilms' tumor suppressor gene (WT1) plays crucial roles in urogenital and gonadal development. Germline mutations of WT1 have been reported in patients with Denys-Drash syndrome (DDS) and Frasier syndrome (FS). Based on clinical overlaps reported to date, it has been suggested that these two syndromes should be considered as part of a spectrum of diseases caused by WT1 gene mutations, rather than as separate diseases. We report a new mutation in an intron 9 splice acceptor site (IVS -1G-->) in a Japanese 46,XY male patient with focal segmental glomerulosclerosis (FSGS) and bilateral cryptorchism. The clinical phenotype of this patient resembled FS without male pseudohermaphroditism. Interestingly, although the patient's right kidney was diagnosed with FSGS, his left kidney showed severe hypoplasia. There are no previous case reports of FSGS and renal hypoplasia in the same individual with a WT1 mutation. The findings for this case further suggest that the renal phenotype has various manifestations and is not always decided by the type of WT1 mutation. The possibility that the position of the WT1 mutation may influence the course of the nephropathy should be evaluated in a larger patient cohort.
Assuntos
Transtornos do Desenvolvimento Sexual/genética , Glomerulosclerose Segmentar e Focal/genética , Mutação , Sítios de Splice de RNA/genética , Proteínas WT1/genética , Pré-Escolar , Criptorquidismo/complicações , Criptorquidismo/genética , Síndrome de Denys-Drash/genética , Transtornos do Desenvolvimento Sexual/complicações , Síndrome de Frasier/genética , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Íntrons/genética , Rim/patologia , Masculino , Análise de Sequência de DNARESUMO
Idiopathic infantile arterial calcification (IIAC) is a life-threatening disorder in young infants. Cardiovascular symptoms are usually apparent within the first month of life. The symptoms are caused by calcification of large and medium-sized arteries, including the aorta, coronary arteries, and renal arteries. Most of the patients die by 6 months of age because of heart failure. Recently, homozygous or compound heterozygous mutations for the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene were reported as causative for the disorder. ENPP1 regulates extracellular inorganic pyrophosphate (PPi), a major inhibiter of extracellular matrix calcification. Two Japanese patients with IIAC were studied. One, from first-cousin parents, showed a typical clinical course. The onset in the second patient was late. Both of the patients were clinically compatible for IIAC; arterial calcification was shown, and hypertension was prominent. We sequenced all the exons and exon-intron boundaries of the gene and measured nucleotide pyrophosphohydrolase (NPPH) activity of ENPP1. Homozygous Arg730Stop was detected in the typical IIAC patient. The mutation was a novel nonsense mutation and not detected in 60 healthy controls. His NPPH activity was 4% of normal. On the other hand, the late-onset patient was not shown to have any mutations. NPPH activity in this patient was 70% of normal. We confirmed that ENPP1 was also responsible for the Japanese patient with IIAC. The atypical late-onset phenotype may not be associated with ENPP1 abnormalities. IIAC is considered to be a clinically and genetically heterogeneous disorder.