Clinical and Genetic Analysis in Congenital Hypothyroidism Due to Thyroid Dysgenesis.
Clinical and Genetic Analysis in Congenital Hypothyroidism Due to Thyroid Dysgenesis.
Congenital hypothyroidism (CH) is a rare disease that affects 1 in 3500 newborn. This
 condition is detected consistently since the late 1970s in France, which has led to early
 care and a significant improvement in prognosis and intellectual stature of these children.
 However neurodevelopmental disorders persist in 10-15% of cases. More associated diseases
 have been reported in approximately 10% of cases. These observations are in most cases poorly
 understood. The family nature of the CH is now well recognized and a dozen genes involved up
 to now. However, in the majority of cases (HC not due to a disorder of the organification of
 iodine), few mutations have been found in the reported number of patients (5-10%), suggesting
 the involvement of other genes. Some of the genes have been implicated in particular specific
 syndromic forms but many pathological associations remain unexplained. Also, a more complete
 genetic elucidation of CH would enable a better understanding of its etiology and thus its
 risk of familial recurrence (frequently asked questions by parents of children with CH) and
 secondly the presence of associated pathologies.

 Main goal: to describe the population with CH (not due to a disorder of the organification of
 iodine) not only on clinical, biological and radiological (phenotypic analysis) but also on
 the genetic level to establish a genotype / phenotype correlation.
Congenital hypothyroidism (CH) is a rare disease that affects 1 in 3500 newborn. This
 condition is detected consistently since the late 1970s in France, which has enabled early
 care and a significant improvement of the intellectual stature and prognosis of these
 children. However neurodevelopmental disorders persist in 10-15% of cases. More associated
 pathologies have been reported in nearly 10% of cases. These observations are in most cases
 poorly understood. The family nature of the HC is now well accepted and a dozen genes is now
 involved. However in the majority of cases (HC not due to a disorder of the organification of
 iodine), few mutations have been found relative to the number of patients (5-10%), suggesting
 the involvement of other genes. Some of the genes have been implicated in such specific
 syndromic forms but many pathological associations remain unexplained. Also, a more complete
 elucidation of genetic HC enable a better understanding of its etiology and thus share the
 risk of familial recurrence (frequently asked by parents of children with questions) and
 secondly the presence of comorbidities.

 Main objective: To describe the population with HC (not due to a disorder of the
 organification of iodine) not only on clinical, biological and radiological (phenotypic
 analysis) but also at the genetic level to establish a genotype / phenotype correlation.

 Secondary objectives:

 1. study the frequency of malformations and / or pathological associations in patients with
 HC

 2. identify groups of patients with syndromic forms in whom early treatment may improve the
 prognosis of children

 3. to search for mutations in genes known to be involved in the pathology

 4. to search for new loci and / or genes involved

 5. to determine the optimal genetic strategy to adopt before a HC case.

 Inclusion criteria:

 - Patient: Newborn (0-27 days) or infant (28 days-23 months), or a child or adult with
 congenital hypothyroidism (that is to say with a filter paper TSH > 15 mU / ml and / or a
 serum TSH> 10 mU / ml) diagnosed in the first months of life, regardless of age, sex, weight
 and size.

 Subjects with blood levels of free thyroid hormones (FT3 and FT4) in the standards are
 described as having subclinical hypothyroidism.

 If treatment with L-thyroxine has been stopped without relapse (that is to say, always with a
 TSH <5 mU / ml with different controls), hypothyroidism is called transient, whatever the age
 of discontinuation.

 -  No earlier or neonatal goitre by palpation or ultrasound examinations

 -  negative perchlorate test (ie rate of iodine salting <10% at 2 hours from the injection
 of the perchlorate) when the thyroid gland in place

 -  No self-immunity against thyroid in children and / or in her mother (defined by a
 antithyroperoxidase presence of antibodies and / or thyroglobulin)

 -  Signature of free and informed consent by the patient or his legal representative

 -  Affiliate or enjoying a social security system

 Non-inclusion criteria:

 -  Presence of antithyroid autoimmunity in children and / or mother markers
 (antithyroperoxidase presence of antibodies and / or thyroglobulin)

 -  Goiter by neonatal palpation or ultrasound examinations

 -  positive perchlorate test (ie. decreased rate of iodine> 10% at 2 injection of
 perchlorate)

 Exclusion criteria:

 Patients of foreign origin returned to their country will be excluded from the study, even
 those who are lost to follow or refuse to perform additional tests requested.

 -  Acts / medical examinations carried out in taking care of but usually within the scope
 of the search if not done in the care:

 -  Ultrasound thyroid

 -  Thyroid scintigraphy

 -  Data on thyroid function: minimum values of FT3, FT4 and TSH plasma last blood test and
 current treatment (dose of L-T4)

 -  Data on the current education (or occupation) and level of psychomotor development
 established by the scale of Denver

 -  Data associated diseases: echocardiography and / or existence of heart disease and
 kidney and / or ultrasound existence of renal disease

 -  Clinical examination performed by the clinician investigator geneticist center.

 -  Standard karyotype

 -  Specific Genetic Analysis: TTF1/Nkx2.1; FOXE/TTF2; PAX8, TSHR and Nkx2.5 on blood sample
 for all patients (10 ml EDTA blood)

 -  Search for new genes

 1. cases of consanguineous families, a genome-wide study will be looking for
 homozygous regions shared by affected members (or homozygosity mapping autozygotie
 mapping).

 (in related first degree blood sample of 10 mL EDTA)

 2. for patients with one or more diseases associated with HC, seeking a number
 variation (CNV) of a gene or locus.

 If abnormality found in the patient, blood samples of two parents 10 ml EDTA search CNV
 variation to exclude inherited CNVs.

 350 patients with HC followed by endocrinologists and / or French pediatricians. Note that a
 majority of patients has been identified in the database of more than 10 years in the INSERM
 U845 (Necker Hospital, Paris).

 Planned duration of the test: 42 month Time inclusions: 18 months Duration of follow-up: 2
 years The patient may be contacted with the agreement at any time to perform additional tests
 required and / or a new blood sample for further genetic study.

 Multinational cross-sectional study In a first period, it will accurately describe patients
 phenotypically and in a 2nd period, find a genetic cause. This will be facilitated by the
 presence of DNA already collected for the majority of them in one national bank in France,
 established in laboratory research center U845 (biocollection DC-2008-596, Faculty Necker,
 Paris)

 Primary endpoint:

 -  Etiological type of congenital hypothyroidism: athyrose, ectopia, hemiagnÃ©sie,
 hypoplastic gland in place of normal shape and size

 -  Presence and type of cytogenetic abnormalities and / or genetically presence and type of
 pathology associated with HC

 -  Presence of neuropsychological abnormalities (including delayed psychomotor development)

 Secondary endpoints:

 Will be considered in this chapter all the elements that can cause psychomotor retardation
 (3):

 -  Time management of hypothyroidism

 -  Optimization of the treatment of hypothyroidism: delay normalization of TSH and T4,
 number of TSH> 15 mU / ml during follow-up, adherence

 -  The presence of an earlier complication and / or neonatal

 Statistical analysis will include the following main chapters:

 -  Description of the population (anamnestic data, clinical, hormonal status at diagnosis
 and at follow-up imaging data).

 -  Analysis of the determinants of psychomotor development (see criteria secondary
 outcome).

 -  Data from the genetic study (type of mutated gene and nature of the mutation or genetic
 location of a deletion or duplication) An analysis of the observed association between
 mutations and phenotypes of patients will be performed by the methods of comparison
 genotype frequencies in different groups of subjects (chi-square test or Pearson 2 if
 necessary by the Fisher exact test).

 The hazard ratios associated with the risk of occurrence of each event will be estimated with
 confidence intervals at 95%. Comparisons of events between different mutations will be tested
 using the log-rank test. All tests will be bilateral and a value of p <0.05 is considered
 statistically significant.

 After 42 month, the study will identify the responsible genes in a large proportion of
 patients with congenital hypothyroidism (excluding disorders organification of iodine), to
 establish a genotype-phenotype correlation and propose early genetic screening (through
 systematic newborn screening) to patients and their families. The study of the frequency of
 associated diseases and genetic elucidation will also provide recommendations for early
 treatment (possibly "preventive") from other later predictable and potentially negative
 repercussions associated with hypothyroidism
Inclusion Criteria:

 - Patient: newborn (0-27 days) or infant (28 days 23 months), or child or adult with
 congenital hypothyroidism (that is to say with a TSH > 15 mU / ml at screening on filter
 paper and / or plasma TSH> 10 mU / ml) diagnosed in the first months of life, whatever
 their age, sex, weight and size.

 Subjects with blood levels of free thyroid hormones (FT3 and FT4) in the standards will be
 described as having subclinical hypothyroidism.

 If treatment with L-thyroxine could be stopped without relapse (that is to say, always with
 a TSH <5 mU / ml with different controls), hypothyroidism is said to be transient, whatever
 the age of discontinuation of treatment.

 -  No pre or neonatal goitre by palpation or ultrasound thyroid

 -  negative perchlorate test (ie decreased rate of iodine captation <10% at 2h injection
 of perchlorate) when the thyroid gland in place

 -  No self-immunity known to thyroid in children with and / or his mother (defined by a
 antithyroperoxidase antibodies and / or antithyroglobulin)

 -  Signature of free and informed consent by the patient or his legal representative

 -  Affiliation or enjoying a social security system

 Exclusion Criteria:

 -  Presence of markers antithyroid autoimmunity in children and / or mother
 (antithyroperoxidase antibodies and / or antithyroglobulin)

 -  Pre or neonatal goiter on palpation or ultrasound thyroid

 -  Test positive perchlorate (ie salting rate of iodine> 10% at 2 injection perchlorate)

 -  Patients of foreign origin returned to their country will be excluded from the study.