Clinical trial NCT05858606: Multidisciplinary Evaluation and a Genome-wide Analysis in a Cohort of Idiopathic Short Stature Patients
Official title: Pilot Study of Ethiology Research by a Multidisciplinary Evaluation Then a Genome-wide Analysis in a Cohort of Idiopathic Short Stature Patients
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Idiopathic Short Stature
Keywords: idiopathic short stature
whole genome analysis
monogenic conditions
syndromic disorders
skeletal dysplasia
Lead sponsor: University Hospital, Montpellier
Sponsor class: OTHER
First posted: 2023-05-15
Enrollment: 200
Sex: ALL
Minimum age (years): 4
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Our 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. We propose to perform a two-step study. 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.
Primary purpose: DIAGNOSTIC

Brief summary: Our 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. We propose to perform a two-step study. 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.

Detailed description: 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. We could therefore expect to have a much higher proportion of diagnosed patients with more standardized procedures both clinical and genetic. 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.

Our 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. We propose to perform a two-step study. 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.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: proportion of patients with authentified idiopathic short stature after multidisciplinary clinical-radiological analysis
timeFrame: 3 years
Secondary outcomes:
measure: Genome positivity rate
timeFrame: 3 years
measure: Rate of positivity of molecular analyses prescribed as part of the care following the PCR
timeFrame: 3 years
measure: Rate of modification of management by the results of genome analysis
timeFrame: 3 years
measure: Type of change in management due to genome analysis results
timeFrame: 3 years
measure: Rate of change in management by results of molecular analysis performed in a patient-care context for those with non-idiopathic short stature
timeFrame: 3 years
measure: Type of management modification by molecular analysis resultscare context for those with non-idiopathic short stature
timeFrame: 3 years
measure: Parental satisfaction assessed via a visual analog scale (Teleconsultation (1) and (2))
timeFrame: 3 years
measure: Variants within the same gene identified in at least 2 patients by whole genome analysis in the group of 30 patients with authentified idiopathic short stature in whom genome analysis has been performed
timeFrame: 3 years
Other outcomes:
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