RESUMEN
BACKGROUND: As syndromic short stature and overgrowth are heterogeneous and the list of causative genes is rapidly expanding, there is an unmet need for identifying genetic causes based on conventional gene testing or karyotyping. Early diagnosis leads to the proper management of the patient and providing genetic counseling for family members at risk in a timely manner. MATERIALS AND METHODS: We conducted targeted exome sequencing to identify the genetic causes of undiagnosed syndromic short stature or overgrowth in 15 pediatric patients from 13 families in Korea. We applied targeted exome sequencing using the Next Seq platform and a TruSight One panel. RESULTS: Among the 13 families, 6 different disorders in 8 patients with short stature or overgrowth were identified, and the diagnostic yield was 46.2%. One boy with overgrowth had a TGFB3 gene mutation. In the short stature group, Coffin-Lowry syndrome (CLS), trichorhinophalangeal syndrome, DYRK1A haploinsufficiency syndrome, short stature with optic atrophy and Pelger-Huët anomaly syndrome with recurrent hepatitis, and type 4 Meier-Gorlin syndrome were identified. One CLS patient had a co-existing monogenic disease, congenital glaucoma, caused by the compound heterozygote mutations of the CYP1B1 gene. CONCLUSION: Targeted exome sequencing is a powerful method for diagnosing syndromic growth disorders. It enables us to understand molecular pathophysiology and investigate new treatments for growth disorders.
Asunto(s)
Enanismo/diagnóstico , Exoma , Predisposición Genética a la Enfermedad , Gigantismo/diagnóstico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Factor de Crecimiento Transformador beta3/genética , Niño , Preescolar , Enanismo/clasificación , Enanismo/genética , Femenino , Expresión Génica , Gigantismo/genética , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Mutación , Linaje , Estudios Prospectivos , República de Corea , Quinasas DyrKRESUMEN
Growth hormone (GH) treatment is approved by the US Food and Drug Administration (FDA) not only for GH deficiency (GHD) but also for other childhood growth disorders with growth failure and/or short stature. GHD is the most frequent endocrine disorder presenting with short stature in childhood. During neonatal period, metabolic effects due to congenital GHD require a prompt replacement therapy to avoid possible life-threatening complications. In childhood and adolescence, growth impairment is the most evident effect of GHD and early treatment has the aim of restore normal growth and to reach normal adult height. We reassume in this review the conditions causing GHD and the diagnostic challenge to reach an early diagnosis, and an early treatment, necessary to obtain the best results. Finally, we summarize results obtained in clinical studies about pediatric patients with GHD treated at an early age, in which a marked early catch-up growth and a normalization of adult height were obtained.
Asunto(s)
Enanismo Hipofisario/tratamiento farmacológico , Terapia de Reemplazo de Hormonas , Hormona de Crecimiento Humana/uso terapéutico , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Ensayos Clínicos como Asunto , Estudios de Cohortes , Diagnóstico por Imagen , Enanismo/clasificación , Enanismo/diagnóstico , Enanismo/tratamiento farmacológico , Enanismo/epidemiología , Enanismo Hipofisario/congénito , Enanismo Hipofisario/diagnóstico , Enanismo Hipofisario/epidemiología , Enanismo Hipofisario/genética , Diagnóstico Precoz , Humanos , Hipoglucemia/congénito , Hipoglucemia/tratamiento farmacológico , Enfermedades Hipotalámicas/complicaciones , Enfermedades Hipotalámicas/diagnóstico , Lactante , Recién Nacido , Estudios Multicéntricos como Asunto , Enfermedades de la Hipófisis/complicaciones , Enfermedades de la Hipófisis/diagnóstico , Evaluación de Síntomas , Resultado del TratamientoRESUMEN
BACKGROUND: Desbuquois dysplasia (DD) is a recessively inherited condition characterised by short stature, generalised skeletal dysplasia and advanced bone maturation. DD is both clinically and radiographically heterogeneous, and two subtypes have been distinguished based on the presence (type 1) or absence (type 2) of an accessory metacarpal bone. In addition, an apparently distinct variant without additional metacarpal bone but with short metacarpals and long phalanges (Kim variant) has been described recently. Mutations in the gene that encodes for CANT1 (calcium-activated nucleotidase 1) have been identified in a subset of patients with DD type 1. METHODS: A series of 11 subjects with DD from eight families (one type 1, two type 2, five Kim variant) were examined for CANT1 mutations by direct sequencing of all coding exons and their flanking introns. RESULTS: Eight distinct mutations were identified in seven families (one type 1, one type 2 and all 5 Kim variant): three were nonsense and five were missense. All missense mutations occurred at highly conserved amino acids in the nucleotidase conserved regions of CANT1. Measurement of nucleotidase activity in vitro showed that the missense mutations were all associated with loss-of-function. CONCLUSION: The clinical-radiographic spectrum produced by CANT1 mutations must be extended to include DD type 2 and Kim variant. While presence or absence of an additional metacarpal ossification centre has been used to distinguish subtypes of DD, this sign is not a distinctive criterion to predict the molecular basis in DD.
Asunto(s)
Mutación Missense/genética , Nucleotidasas/genética , Secuencia de Aminoácidos , Animales , Células COS , Preescolar , Chlorocebus aethiops , Anomalías Craneofaciales/clasificación , Anomalías Craneofaciales/complicaciones , Anomalías Craneofaciales/diagnóstico por imagen , Anomalías Craneofaciales/genética , Enanismo/clasificación , Enanismo/complicaciones , Enanismo/diagnóstico por imagen , Enanismo/genética , Mano/diagnóstico por imagen , Deformidades Congénitas de la Mano/complicaciones , Deformidades Congénitas de la Mano/diagnóstico por imagen , Humanos , Inestabilidad de la Articulación/clasificación , Inestabilidad de la Articulación/complicaciones , Inestabilidad de la Articulación/diagnóstico por imagen , Inestabilidad de la Articulación/genética , Datos de Secuencia Molecular , Nucleotidasas/química , Osificación Heterotópica/clasificación , Osificación Heterotópica/complicaciones , Osificación Heterotópica/diagnóstico por imagen , Osificación Heterotópica/genética , Polidactilia/clasificación , Polidactilia/complicaciones , Polidactilia/diagnóstico por imagen , Polidactilia/genética , Radiografía , Alineación de SecuenciaAsunto(s)
Enanismo/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/fisiología , Tipificación del Cuerpo , Desarrollo Óseo/fisiología , Enanismo/clasificación , Enanismo/patología , Enanismo/fisiopatología , Humanos , Mutación , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
BACKGROUND: In total, 43 patients having short stature syndrome in 37 Yakut families with autosomal recessive prenatal and postnatal nonprogressive growth failure and facial dysmorphism but with normal intelligence have been identified. METHODS: Because Yakuts are considered as a population isolate and the disease is rare in other populations, genomewide homozygosity mapping was performed using 763 microsatellite markers and candidate gene approach in the critical region to identify the causative gene for the short stature syndrome in Yakut. RESULTS: All families shared an identical haplotype in the same region as the identical loci responsible for 3-M and gloomy face syndromes and a novel homozygous 4582insT mutation in Cullin 7 (CUL7) was found, which resulted in a frameshift mutation and the formation of a subsequent premature stop codon at 1553 (Q1553X). Yakut patients with short stature syndrome have unique features such as a high frequency of neonatal respiratory distress and few bone abnormalities, whereas the clinical features of the other Yakut patients were similar to those of 3-M syndrome. Furthermore, abnormal vascularisation was present in the fetal placenta and an abnormal development of cartilage tissue in the bronchus of a fetus with CUL7 mutation. CONCLUSION: These findings may provide a new understanding of the clinical diversity and pathogenesis of short stature syndrome with CUL7 mutation.
Asunto(s)
Codón sin Sentido , Proteínas Cullin/genética , Enanismo/genética , Etnicidad/genética , Cara/anomalías , Retardo del Crecimiento Fetal/genética , Mutagénesis Insercional , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Adolescente , Adulto , Bronquios/embriología , Bronquios/patología , Niño , Preescolar , Enanismo/clasificación , Enanismo/etnología , Etnicidad/etnología , Femenino , Retardo del Crecimiento Fetal/etnología , Retardo del Crecimiento Fetal/patología , Efecto Fundador , Genes Recesivos , Haplotipos/genética , Humanos , Recién Nacido , Masculino , Fenotipo , Placenta/irrigación sanguínea , Placenta/patología , Síndrome de Dificultad Respiratoria del Recién Nacido/etnología , Siberia/epidemiología , SíndromeRESUMEN
Microcephalic osteodysplastic primordial "dwarfism" (MOPD) is a group of disorders similar to Seckel syndrome. Three subtypes (types I-III) have been reported. We report here the first autopsy case of MOPD type II. The patient was a Japanese girl with typical clinical and radiological manifestations of MOPD type II. The manifestations included severe intrauterine and postnatal growth failure, microcephaly, a distinctive facial appearance, micromelia, brachytelephalangy, coxa vara, and V-shaped metaphyses of the distal femora. Other than small cerebral hemispheres, no neuropathological abnormalities were found. Chondro-osseous histology showed thinning of the growth plate, ballooned chondrocytes, reduced cellularity, lack of zonal and columnar formations, and poor formation of primary trabeculae. These findings suggest that impairment of chondrocytic formation and differentiation is the major pathogenesis of MOPD type II.
Asunto(s)
Anomalías Múltiples/genética , Anomalías Múltiples/patología , Adulto , Pueblo Asiatico , Autopsia , Peso al Nacer , Cesárea , Enanismo/clasificación , Enanismo/genética , Enanismo/patología , Femenino , Humanos , Lactante , Recién Nacido , Japón , Masculino , Microcefalia/clasificación , Microcefalia/genética , Microcefalia/patologíaRESUMEN
We describe a case of neonatal lethal dwarfism characterised by short trunk, short, stick-like tubular bones, deficient ossification of the axial skeleton and broad, sclerotic horizontal ribs. Two similar cases have previously been reported as examples of the Neu-Laxova syndrome. However, the radiological findings of the Neu-Laxova syndrome, as reported in 16 out of 40 documented cases, show a heterogeneous pattern of minor features, which differ distinctively from those found in the previous two cases and by us. A literature research did not reveal similar cases, and we therefore suggest that our case, together with the two previous cases, may represent a new distinctive form of neonatal lethal dwarfism.
Asunto(s)
Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Enanismo/clasificación , Enfermedades del Desarrollo Óseo/complicaciones , Enanismo/diagnóstico por imagen , Femenino , Muerte Fetal , Humanos , Recién Nacido , Radiografía , SíndromeRESUMEN
We report two unrelated infants with cephaloskeletal dysplasia or Taybi-Linder syndrome, also referred to as osteodysplastic primordial dwarfism Type III. They presented with peculiar facial features, microcephaly and skeletal and cerebral abnormalities documented radiographically and with cranial MRI and/or CT. Some dissimilarities were observed in the skeletal findings between the two patients, most likely reflecting phenotypic variability within the same disorder. Some radiographic features were shown to evolve with time in both patients. Also of interest is the unusually long survival of these patients, more than 4 years in the first and of over 6 years in the second.
Asunto(s)
Enanismo/diagnóstico , Factores de Edad , Huesos/diagnóstico por imagen , Preescolar , Enanismo/clasificación , Enanismo/diagnóstico por imagen , Enanismo/mortalidad , Femenino , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Pronóstico , Cráneo/diagnóstico por imagen , Síndrome , Tomografía Computarizada por Rayos XAsunto(s)
Síndrome de Ellis-Van Creveld/genética , Etnicidad/genética , Efecto Fundador , Proteínas/genética , Enfermedades de los Cartílagos/etnología , Enfermedades de los Cartílagos/genética , Relaciones Comunidad-Institución , Consanguinidad , Enanismo/clasificación , Enanismo/etnología , Enanismo/genética , Síndrome de Ellis-Van Creveld/etnología , Síndrome de Ellis-Van Creveld/historia , Etnicidad/historia , Femenino , Finlandia/etnología , Frecuencia de los Genes , Genes Recesivos , Genética de Población , Alemania/etnología , Enfermedades del Cabello/etnología , Enfermedades del Cabello/genética , Historia del Siglo XVIII , Humanos , Intrones/genética , Leucina Zippers/genética , Masculino , Proteínas de la Membrana , Pennsylvania , Suiza/etnología , SíndromeRESUMEN
Torrance, San Diego, and Luton types ("West coast" types) of neonatal platyspondylic short-limbed dwarfism are suspected to be caused by dominant mutations that are obligatorily lethal. We report on an affected mother, who passed the disease to her daughter, confirming dominant disease transmission. Survival of the mother indicates a wider phenotypic spectrum.
Asunto(s)
Enanismo/genética , Genes Letales , Enanismo/clasificación , Resultado Fatal , Femenino , Humanos , Recién NacidoRESUMEN
To further delineate and classify those forms of short trunk dwarfism characterized by multiple vertebral segmentation defects, we analyzed 26 new patients and reviewed 115 described in the literature. Three distinct entities were recognized based on radiographic and clinical findings. Jarcho-Levin syndrome is the lethal autosomal recessive form, characterized by a symmetric crab-like chest. Spondylocostal dysostosis is the benign autosomal dominant condition. Spondylothoracic dysostosis shows considerable clinical and radiographic overlap with spondylocostal dysostosis. Malformations observed in association with multiple vertebral segmentation defects are more common in the sporadic patients. Analysis of the 26 new individuals revealed that the body segment in which these nonvertebral malformations occur corresponds to the site of the vertebral segmentation defects.
Asunto(s)
Enanismo/clasificación , Vertebrados/anomalías , Adolescente , Animales , Niño , Preescolar , Enanismo/patología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Vértebras Torácicas/anomalíasRESUMEN
Seckel syndrome is a clinical picture which associates four main features: intrauterine growth retardation, microcephaly often due to craniosynostosis, orofacial dysmorphology with bird headed appearance and variable mental retardation which is present after several months. Malformations of the central nervous system, limbs, and hair, may also be observed. On the basis of 78 cases reported in the literature, the authors discuss the validity of the morphological features of the syndrome. It is likely that the variability in the expressivity of each symptom explains its heterogeneity. According to the radiological abnormalities, three different forms of the syndrome have been described. Seckel syndrome is a genetic disorder with autosomal recessive inheritance. Its ethiopatogeny remains unclear. Hopefully linkage studies will allow to map the gene in order to determine the underlying abnormal protein.
Asunto(s)
Anomalías Múltiples , Daño Encefálico Crónico/etiología , Enanismo/clasificación , Niño , Diagnóstico Diferencial , Enanismo/etiología , Extremidades/diagnóstico por imagen , Huesos Faciales/anomalías , Femenino , Retardo del Crecimiento Fetal/complicaciones , Humanos , Discapacidad Intelectual/complicaciones , Deformidades Congénitas de las Extremidades , Microcefalia/complicaciones , Embarazo , Radiografía , SíndromeRESUMEN
Two brothers from a black family had microcephaly, short stature, and generalized microdontia. Endocrine and chromosome studies were normal, and mild skeletal manifestations were present. The patients may represent a distinct dental-skeletal dysplasia, possibly osteodysplastic primordial dwarfism type II. Attention to dental manifestations in similar cases may be useful for classification.
Asunto(s)
Enanismo/genética , Microcefalia/genética , Anomalías Dentarias/genética , Adolescente , Niño , Enanismo/clasificación , Humanos , MasculinoRESUMEN
We describe a 22-month-old Japanese girl with severe microcephaly with a prominent nose and a receding chin, developmental delay, marked intrauterine and postnatal dwarfism with limb shortening and brachydactyly, and distinctive radiological changes of the skeleton. The radiological findings include hypoplasia of the short tubular bones, multiple pseudoepiphyses in the bases of the metacarpals, coxa valga, a wide pelvis with iliac flaring, thoracolumbar scoliosis, and disharmonious ossification delay. The clinical and radiological features are somewhat different from those of previously reported cases with osteodysplastic primordial dwarfism. The clinical and radiological manifestations of osteodysplastic primordial dwarfism are reviewed and compared with those in our patient.
Asunto(s)
Enanismo/patología , Enanismo/clasificación , Enanismo/diagnóstico por imagen , Extremidades/diagnóstico por imagen , Cara/anomalías , Femenino , Humanos , Lactante , Deformidades Congénitas de las Extremidades , Microcefalia/patología , Pelvis/anomalías , Pelvis/diagnóstico por imagen , Radiografía , Escoliosis/diagnóstico por imagenAsunto(s)
Enanismo Hipofisario/genética , Hormona del Crecimiento/deficiencia , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Enanismo/clasificación , Enanismo/etiología , Enanismo Hipofisario/fisiopatología , Hormona del Crecimiento/genética , Hormona del Crecimiento/inmunología , Hormona Liberadora de Hormona del Crecimiento/deficiencia , Hormona Liberadora de Hormona del Crecimiento/genética , Humanos , Hipopituitarismo/genética , Sistema Hipotálamo-Hipofisario/fisiopatología , Adenohipófisis/anomalías , Adenohipófisis/fisiopatología , Eliminación de SecuenciaRESUMEN
A male infant with "classical" Seckel syndrome and a girl with osteodysplastic primordial dwarfism type II are described. The boy with classical Seckel syndrome had severe brain dysplasia, a finding hitherto unreported in patients with this syndrome. The patient with osteodysplastic dwarfism type II had skeletal abnormalities including lumbar scoliosis, a small and high pelvis, metaphyseal flaring of the distal radii and ulnae, V-shaped metaphyseal flaring of the distal femorae, and short metacarpals and phalanges. The mother of this girl was short, microcephalic, and had disproportionately short forearms and legs. In view of this, dominant inheritance of the disease was suggested.
Asunto(s)
Enanismo/genética , Microcefalia/genética , Anomalías Múltiples/genética , Pueblo Asiatico , Niño , Enanismo/clasificación , Femenino , Regulación de la Expresión Génica , Genes Dominantes , Humanos , Lactante , Japón , Masculino , SíndromeRESUMEN
Type II primordial microcephalic dwarfism is a rare form of bird-headed dwarfism individualized in 1982 by Majewski. A case in a female patent with completed growth illustrates the main features, which include severe growth retardation (greater than 4 SD reduction in height) of prenatal onset, short limbs, coxa vara with epiphysiolysis of the hips, metaphyseal flaring and, in some instances, shortness of the ulnas and curvature of the radiuses. A genetic cause (with autosomal recessive inheritance) is very likely. A number of features in the case reported herein may be of pathogenetic relevance: growth hormone levels were elevated before closure of the epiphyses and normal thereafter, no growth spurt occurred at puberty, polycystic ovaries with hirsutism developed after puberty, and surgical wound healing was unusually slow.
Asunto(s)
Enanismo/clasificación , Microcefalia/clasificación , Adolescente , Antropometría , Enanismo/sangre , Enanismo/diagnóstico por imagen , Enanismo/genética , Enanismo/patología , Femenino , Hormona del Crecimiento/sangre , Humanos , Microcefalia/sangre , Microcefalia/diagnóstico por imagen , Microcefalia/genética , Microcefalia/patología , Pubertad , RadiografíaRESUMEN
A case of microcephalic, osteodysplastic, primordial dwarfism (cephaloskeletal dysplasia of Taybi and Linder) is reported. This rare disease is characterised by unique clinical appearances and diagnostic radiographic findings. It is also associated with distinctive brain abnormalities. The latter include micrencephaly, lissencephaly, corpus callosum aplasia/agenesis and unusual histological brain abnormalities.