Multidisciplinary Evaluation and a Genome-wide Analysis in a Cohort of Idiopathic Short Stature Patients

Официальное название

Pilot Study of Ethiology Research by a Multidisciplinary Evaluation Then a Genome-wide Analysis in a Cohort of Idiopathic Short Stature Patients

Обзор

This trial aims to evaluate the prevalence of idiopathic short stature among children whose growth is above -2,5SD (AFPA- CRESS/Inserm -CompuGroup Medical 2018 curve) or above -2SD of the parental target size (taking child gender into account), after exclusion of classical pediatric and endocrinologic pathologies, and to evaluate the prevalence of monogenic causes of idiopathic short stature. A two-step study will be performed. The first one consists in a standardized multidisciplinary clinico-radiological evaluation of those children to evaluate the real prevalence of idiopathic short stature (ISS) among these patients. The second step consists in performing a whole genome sequencing analysis in the 30 first patients for whom the diagnosis of ISS is confirmed.

Подробное описание

Detailed description: Establishing the etiological diagnosis of short stature is an important step to guide the therapeutic management of patients and to propose appropriate genetic counseling. Short stature can be a symptom of many pathologies. However, in the majority of cases (80%), no specific etiology is found during a pediatric clinical investigation. In this case, the diagnosis of "idiopathic" short stature is performed. However, the diagnostic and therapeutic management of short stature after exclusion of classical pediatric causes is extremely heterogeneous and there are currently no consensual recommendations. A substantially higher proportion of diagnosed patients is therefore expected, along with more standardized clinical and genetic procedures. Additionally, in recent years, new methods of genetic investigation (gene panel, whole exome or whole genome sequencing analysis) have made it possible to identify many genetic variants associated with apparently isolated short stature. So far, none of the publications reporting next-generation sequencing analysis have focused on patients with authentic idiopathic short stature, i.e. without associated bone anomalies or syndromic features, and are often focused on only a subset of target genes.

This trial aims at estimating the prevalence of idiopathic short stature among children whose growth is above -2,5SD (AFPA- CRESS/Inserm -CompuGroup Medical 2018 curve) or above -2SD of the parental target size, after exclusion of classical pediatric and endocrinologic pathologies, and to evaluate the prevalence of monogenic causes of idiopathic short stature. A two-step study will be performed. The first one consists in a multidisciplinary clinico-radiological evaluation of those children to evaluate the real prevalence of idiopathic short stature (ISS) among these patients. The second step consists in performing a whole genome sequencing analysis in the 30 first patients for whom the diagnosis of authentic ISS is confirmed.

All patients will have:

* a pre-inclusion visit * an inclusion visit after which the multidisciplinary clinico-radiological evaluation will be held

This analysis will assign patients to the diagnosis of either:

1. non-idiopathic short stature (diagnosis of constitutional bone disease or syndromic disorder) 2. authentic idiopathic short stature

A teleconsultation (1) to explain to the parents the conclusions of the multidisciplinary clinico-radiological evaluation.

This teleconsultation will be followed for all patients in the "non-idiopathic short stature" group, by a visit to take samples for genetic analysis in the context of clinical care, followed by a teleconsultation (2) to give them and explain the results

This teleconsultation will be followed for the first 30 patients in the "authentified idiopathic short stature" group, by a visit to take samples for whole genome analysis in the context of research, followed by a teleconsultation (2) to return the results.

Вмешательства

• Диагностический тест Evaluation of the prevalence of truly (authentified) idiopathic short stature after multidisciplinary clinico-radiological evaluation
  1. pre-inclusion consultation 2. inclusion consultation * personal history * height, weight, cranial perimeters, and spans of both parents * clinical examination of the child * photographs of the child * additional X-rays
• Процедура analysis in a multidisciplinary consultation meeting via a secure platform (ShareConfrère) for evaluation by multidisciplinary team
  multidisciplinary team (geneticist, orthopedist, radiologist, pediatric endocrinologist) which will assign each patient an orientation: * either to the non idiopathic short stature group (syndromic diagnostic orientation or to a constitutional bone pathology) * or to the authentified idiopathic short stature group
• Генная терапия Whole genome analysis for authentified idiopathic short stature
  For the first 30 patients included in the authentified idiopathic short stature group, a whole genome analysis in trio (child + parents) will be performed as part of the research. For these 30 patients in the authentified idiopathic short stature group, the teleconsultation carried out for the submission of the multidisciplinary consultation meeting conclusions will make it possible to establish the family tree, to explain the interest and limits of the analysis, and to submit the consents dedi

Первичные конечные точки

• proportion of patients with authentified idiopathic short stature after multidisciplinary clinical-radiological analysis [Срок оценки: 3 years]

Вторичные конечные точки (8)

• Genome positivity rate [Срок оценки: 3 years]
• Rate of positivity of molecular analyses prescribed as part of the care following the PCR [Срок оценки: 3 years]
• Rate of modification of management by the results of genome analysis [Срок оценки: 3 years]
• Type of change in management due to genome analysis results [Срок оценки: 3 years]
• Rate of change in management by results of molecular analysis [Срок оценки: 3 years]
• Type of management modification by molecular analysis resultscare context for those with non-idiopathic short stature [Срок оценки: 3 years]
• Parental satisfaction [Срок оценки: 3 years]
• Variants within the same gene identified in at least 2 patients by whole genome analysis [Срок оценки: 3 years]

Критерии участия

Критерии включения

• Children aged 4 to 18 years
• 2 sexes
• Height less than -2.5DS (standard deviations of the AFPA- CRESS/Inserm -CompuGroup Medical 2018 curve) or less than -2DS of the TCP (parental target height, corresponding to the average of parental heights +6.5 cm in boys, -6.5 cm in girls)
• Normal karyotype + FISH SHOX for girls
• Previously performed:celiac disease antibodies, WBC-platelets, CRP, blood ionogram, creatinine, blood calcium, blood phosphorus, ASAT, ALAT, PAL, PTH, TSH, T4L, growth hormone test normal according to the standards of the laboratory of the CHU of Montpellier
• Acceptance of X-rays, in addition to those already performed as part of the care, which will not be repeated if necessary: spine front and profile, pelvis front, 1 upper limb front, 1 lower limb front F, hands and feet front
• Acceptance of photographs: whole body with underwear, face face and profile, 2 faces of hands; feet, face
• Acceptance of blood samples for the child and the 2 parents (trio)
• Consent signed by both parents

Критерии исключения

• Intellectual disability (IQ below 70)
• Cardiac, renal, digestive or cerebral malformation, cleft lip or palate, hearing or visual impairment, epilepsy
• Renal or cardiac insufficiency, digestive or chronic inflammatory pathology
• Previously established genetic diagnosis

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Диагностика

Центры проведения

Франция · 1 центр

• Service de Génétique Médicale - Arnaud de Villeneuve — Montpellier

Идентификаторы

NCT: NCT05858606 · RECHMPL22_0396

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗