Congenital hypothyroidism (CH) is a disease related to insufficient thyroid hormone secretion by the thyroid gland. It affects about 1 in 3,000 children and is the leading cause of preventable mental retardation. Its incidence is increasing in France, 1/2 897 in 2015 and 1/2 631 in 2021.

In 67% of cases congenital hypothyroidism is caused by thyroid dysgenesis, either due to a lack of migration during embryonic development or by thyroid hypoplasia or agenesis. The remaining 33% is due to a hormone synthesis disorder. There are also very rare cases of congenital hypothyroidism of central origin (pituitary or hypothalamic).

The biological marker for this disease is TSH. Its determination by immunofluorescence assay, allows the early diagnosis of congenital hypothyroidism and the initiation of L-thyroxine treatment before the child presents symptoms of the disease. The treatment initiated in the first two weeks of life allows the child to develop his or her full intellectual potential, thus justifying neonatal screening. Following the diagnosis of congenital hypothyroidism, the child will be monitored by a pediatric endocrinologist, who will initiate and adapt the treatment, which should be administered once a day, orally, always at the same time, in order to minimize possible forgetfulness.

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>> ORPHA 442

>> ORPHA 95717

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>> Stoupa A et al. Dépistage néonatal des endocrinopathies. Endocrinologie Pédiatrique 2022 ; Les dix points clés en Endocrinologie pédiatrique : chapitres 5 : p 39-44.

Congenital adrenal hyperplasia (CAH) is due to a disturbance in the functioning of the adrenal glands.

The adrenal glands are located above the kidneys and produce several important hormones: cortisol (glucocorticoid) which plays an important role in sugar metabolism and in the fight against fatigue and stress, and aldosterone (mineralocorticoid) which is involved in regulating the movement of water and salt in the body. They also secrete small amounts of male hormones (testosterone).

Congenital adrenal hyperplasia is most commonly associated with a deficiency of the enzyme 21-β-hydroxylase, which leads to decreased production of aldosterone and cortisol, and an accumulation of precursor hormones, such as 17-hydroxy-progesterone (17OHP), which leads to overproduction of testosterone and other male hormones. This condition, which theoretically affects one in 15,000 newborns, can lead to dehydration due to salt loss in the first weeks of life, warranting neonatal screening, and to abnormalities of the external genitalia found at birth in a young girl.

An increase in the blood concentrations of 17OHP, assayed by immunofluorescence, makes it possible to suspect congenital adrenal hyperplasia. Due to the hormonal deficit in aldosterone and cortisol, the child will be prescribed two hormones: hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid). Salt (sodium chloride, NaCl) is also added in the form of capsules or sachets. This treatment must be adapted to each child, and it must be daily, in 2 or 3 doses, at regular times. The dose of the treatments is adjusted by the pediatric endocrinologist according to the clinical examination (weight, height, pubertal development) and biological controls (natremia, kalemia, 17OHP, renin, delta-4 androstenedione, testosterone). In case of increased needs, the dose of hydrocortisone should be increased, doubling or tripling the usual dose.

Appropriate hormonal treatment can cope with these disorders and avoid their consequences. It must be implemented from birth.

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>> ORPHA : 90794

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>> Houang M et al. Analysis of a pitfall in congenital adrenal hyperplasia newborn screening: evidence of maternal use of corticoids detected on dried blood spot. Endocr Connect. 2022 Jun 15;11(6):e220101.

>> Stoupa A et al. Dépistage néonatal des endocrinopathies. Endocrinologie Pédiatrique 2022 ; Les dix points clés en Endocrinologie pédiatrique : chapitres 5 : p 39-44.

Sickle cell disease is an inherited disease caused by an abnormality of hemoglobin (Hb), a protein contained in the red blood cell. Affected people generally suffer from chronic anemia and painful attacks, and are more susceptible to infections. Transmission occurs when both parents are carriers of the disease gene, even if they are not sick (healthy carriers).

In France, Île-de-France is the most affected region (excluding DOM-TOM) with 1 newborn reached out of 700 births. This disease mainly affects populations of Mediterranean, African and Caribbean origin.

In the event of a positive neonatal screening by HbS detection using MALDI-TOF (Matrix Assisted Laser Desorption/Ionization-Time-of-Flight) mass spectrometry or cation-exchange high-performance liquid chromatography (CE-HPLC), a check is carried out on the same blotter using either CE-HPLC or agarose gel isoelectrofocusing. The parents and the newborn will be called in for tests to confirm the diagnosis and organize care for the newborn in a rare diseases reference center or a competence center. Screening thus enables the early initiation of appropriate follow-up and prevention. Parents will also be informed of the risk of the disease for their other children.

>> ORPHA : 232

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Cystic fibrosis (CF) is the most common multi-organ genetic disease in the Caucasian population, and affects approximately one in 3,500 children in France. It is autosomal recessive. It is linked to a dysfunction of the CFTR protein (Cystic Fibrosis Transmembrane conductance Regulator), which ensures the transport of the chloride ion through the apical membrane of epithelial cells, located in particular on the surface of the bronchi and pancreatic ducts, but also at the level of other organs (sweat gland, hepatic, vas deferens, etc…). Sweat too rich in chlorides leaves a salty sensation when kissing the child.

The correct function of CFTR allows a good water-electrolyte balance on each side of the membrane. The good hydration of the mucous secretions allows the vibratile cilia to beat on the surface of the bronchial epithelial cells, which constantly brings the inhaled impurities and microorganisms outwards. When the CFTR protein is altered, the secretions become viscous, thick (thick mucus disease) and mucociliary clearance decreased. This leads to a vicious circle between obstruction – inflammation – bacterial colonization – pulmonary fibrosis, leading to progression to respiratory failure.

Sometimes cystic fibrosis can show itself at birth as a neonatal bowel obstruction (NBO) (meconium ileus) which requires surgical or medical treatment (enemas). Low birth weight may be present. The digestive enzymes secreted by the pancreas no longer reach the intestine and digestion is damaged. The child may have diarrhea and he/she is not getting enough weight.

In the pancreas, the obstruction of the ducts is accompanied by an increase in the blood of pancreatic enzymes, in particular trypsin, which are responsible for digestion. The assay of ImmunoReactive Trypsinogen (IRT) by immunofluorescence makes it possible to suspect the disease. But the increase in IRT is not specific to cystic fibrosis. To make the screening more specific, genetic research for a mutation in the CFTR gene will be carried out if the parents’ consent has been signed on the blotter at the maternity hospital. In the event of a positive cystic fibrosis screening, the parents will be called to a cystic fibrosis resource and competence center to perform the sweat test, the most sensitive and specific biological test for the disease.

Nutritional care (based on pancreatic extracts) and respiratory (physiotherapy, antibiotic therapy adapted if necessary) carried out early with rigorous monitoring will improve the quality of life of the affected child, with a significant extension of his expectation of life.

To date, specific treatments depending on the CFTR mutations present in the patient are proposed to potentiate the capacities of the defective CFTR protein (Ivacaftor, Kalydeco®) and / or to correct CFTR (Lumacaftor / Ivacaftor, Orkambi®; Tezacaftor / Ivacaftor, Symdeko®; forthcoming triple therapy (USA October 2019) Elexacaftor / Tezacaftor / Ivacaftor, Trikafta®) with benefits for the patient in terms of ventilatory capacity, body mass index and quality of life. Early detection makes it possible to initiate appropriate follow-up and treatment, improving the state of health of the children screened.

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>> ORPHA : 586

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>>Munck A et al. Dépistage néonatal de la mucoviscidose en France : aspects pratiques et perspectives. Perfectionnement en Pédiatrie 2019;2:163–171

>> Bienvenu T & Nguyen-Khoa T. Current and future diagnosis of cystic fibrosis: Performance and limitations. Arch Pediatr. 2020 Feb;27 Suppl 1:eS19-eS24

>> Sermet-Gaudelus I et al. [French guidelines for sweat test practice and interpretation for cystic fibrosis neonatal screening]. .Arch Pediatr. 2010;17(9):1349-58.

>> Sermet-Gaudelus I et al. Sweat chloride testing and nasal potential difference (NPD) are primary outcome parameters in treatment with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators. J Pers Med. 2021 Jul 27;11(8):729.

Phenylketonuria is a metabolic disease that affects approximately one in 16,000 newborns. It is related to a total or partial inability of the body to transform one of the constituents of food, phenylalanine, into its by-products. This abnormality leads to an accumulation of phenylalanine in the blood, which is harmful during the brain’s development. In the absence of early treatment, and therefore neonatal screening, this leads to mental retardation and neurological problems, but with a specific diet from the first weeks of life development will be normal.

Phenylalanine is an essential amino acid, constituent of all protein foods, especially of animal origin. A minimum daily amount is required. The diet of these children must therefore provide the baby with the strict quantity he needs, without excess but without deficiency. The « tolerable » quantity for each patient is determined by successive adjustments of the diet. The diet is strict in particular until the age of 8 years, with a target of phenylalaninemia between 3 to 5 mg/dL (i.e. 180 to 300 µmol/L). After this age, the diet may be slightly freer, but taking into account the need to maintain a phenylalanine blood concentration below 20 mg/dL (or 1200 µmol/L).

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>> ORPHA : 716

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>> Polak M, Cheillan D, Nguyen-Khoa T, Lachambre S, de Lonlay P, Arnoux JB, Courapied S, Khemiri A. Nouveautés dans le dépistage néonatal [New developments in neonatal screening]. Rev Prat. 2023 Dec;73(10):1119-1123. French. PMID: 38294483.

Mapple Syrup Urinary Disease (MSUD) is caused by mutations in genes encoding 3 of the subunits of the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex. These mutations lead to an accumulation of branched-chain amino acids (BCAAs, in particular leucine) and their corresponding alpha-keto acids in the blood. In Europe, this disease affects 1 to 4 out of every 250,000 newborns.

The classic MSUD form (residual enzyme activity <2%) manifests itself as early as 6-7 days of age, with feeding difficulties associated with drowsiness. An encephalopathy associating lethargy, stereotyped movements (« boxing » and « bicycling ») progressively sets in, and in the absence of specialized medical care, a deep coma and death will occur over the following days. This potentially fatal risk of coma can recur at any age, during catabolic stress such as infection or prolonged fasting, and sets in over a few hours, preceded by symptoms of intoxication such as vomiting, altered consciousness, ataxia and acute dystonia in infants, and hallucinations, hyperactivity, ataxia and pseudo-ebriety in children and adults.

Classic MSUD in newborns is a medical emergency. The acute phase of management requires aggressive reinforcement of protein anabolism with high caloric intake (use of intravenous glucose and lipids) and a mixture of amino acids without BCAA, combined with isoleucine and valine supplementation. Hemodialysis is often required. Once the infant has stabilized, leucine intake is reintroduced in limited quantities with infant formula, combined with dietary products that supplement the amino acid intake (but without BCAA) with calories, vitamins and minerals. Outpatient monitoring will be close, with weekly BCAA blood tests, and medical and dietary follow-up will be provided by a reference center for hereditary metabolic diseases. The prognosis is favourable when the patient is managed early and intensively, and when follow-up prevents further comas and maintains plasma leucine concentrations between 2 and 5 mg/dL.

>> ORPHA : 511

>> Polak M, Cheillan D, Nguyen-Khoa T, Lachambre S, de Lonlay P, Arnoux JB, Courapied S, Khemiri A. Nouveautés dans le dépistage néonatal [New developments in neonatal screening]. Rev Prat. 2023 Dec;73(10):1119-1123. French. PMID: 38294483.

Tyrosinemia type 1 (HT-1) is an inherited disease of amino acid metabolism characterized by hepatorenal involvement. It is inherited in an autosomal recessive fashion. It is due to a deficiency of fumaryl acetoacetate hydrolase (FAH) in the tyrosine degradation pathway, resulting in inhibition of a key enzyme in porphobilinogen synthesis (delta amino levulinate dehydratase). In Europe, the disease affects 1 to 4 newborns out of every 250,000.

In the acute early infantile form, hepatocellular insufficiency sets in and becomes symptomatic between 15 days and 3 months of age, with vomiting, diarrhea, jaundice, hypoglycemia, edema, ascites and hemorrhagic syndrome. Tubulopathy is associated. The disease can sometimes develop later in childhood into vitamin-resistant rickets linked to tubulopathy and cirrhosis. Untreated, the disease can lead to death from complications of acute hepatocellular failure, or be complicated by pseudoporphyric neurological crises. If treatment is started late, after the age of 6 months, or is poorly monitored, the risk of developing hepatocellular carcinoma during the course of the disease is high.

Treatment is based on the Nitisinone (NTBC) drug in combination with a protein-restricted diet to avoid hypertyrosinemia, and monitoring of liver imaging and alpha-fetoprotein, a sensitive blood marker of hepatocarcinoma. This cancer requires liver transplantation.

Thanks to neonatal screening, mortality and the risk of hepatic carcinoma will be reduced.

>> ORPHA : 882

>> Polak M, Cheillan D, Nguyen-Khoa T, Lachambre S, de Lonlay P, Arnoux JB, Courapied S, Khemiri A. Nouveautés dans le dépistage néonatal [New developments in neonatal screening]. Rev Prat. 2023 Dec;73(10):1119-1123. French. PMID: 38294483.

The disease is an autosomal recessive inherited disorder of methionine metabolism. It is caused by mutations in the CBS gene, which codes for the Cystathionine beta-synthase (CBS) enzyme, which metabolizes homocysteine to cystathionine via the trans-sulfuration pathway of the methionine cycle, using the pyridoxal 5-phosphate cofactor. The 2 other cofactors involved in the methionine re-methylation pathway are vitamin B12 and folic acid.

Clinical manifestations are related to the significant elevation of total homocysteine in plasma. Left untreated, the disease is progressive, manifesting itself as lens ectopia and delayed acquisition in childhood (85% of cases) and skeletal abnormalities (kyphosis, scoliosis, osteoporosis) later in life. Severe thrombo-embolic events (stroke, myocardial infarction, pulmonary embolism) can be life-threatening.

If the disease is diagnosed in a newborn, the aim of treatment is to ensure proper development and prevent the onset of complications.

Some patients have a pyridoxine-sensitive form of the disease (Type I), since this treatment alone can significantly reduce total homocysteine levels. Folic acid and vitamin B12 supplements are sometimes required.

In subjects who do not respond to pyridoxine (Type II, pyridoxine-resistant), the recommended treatment combines a low-methionine diet (i.e. hypoprotein), folic acid, vitamin B12 and anhydrous betaine, the latter of which reduces homocysteine levels by remethylating it into methionine.

Thanks to neonatal screening, very early treatment will help reduce complications, particularly thrombo-embolic ones, and prevent psychomotor retardation.

>> ORPHA : 394

>> Polak M, Cheillan D, Nguyen-Khoa T, Lachambre S, de Lonlay P, Arnoux JB, Courapied S, Khemiri A. Nouveautés dans le dépistage néonatal [New developments in neonatal screening]. Rev Prat. 2023 Dec;73(10):1119-1123. French. PMID: 38294483.

Medium-Chain Acyl-CoA Dehydrogenase deficiency (MCADD) is the most common deficiency of fatty acid beta-oxidation. This deficiency does not manifest itself during intrauterine life. Affected newborns are normal at birth. The vast majority remain asymptomatic. This deficiency causes the body to have difficulty using fat as an energy source.

The consequences for the child can be very serious when the child’s energy needs exceed what the body is able to produce, especially in the case of infections, vomiting or periods of underfeeding. Symptomatic newborns have hypoglycemia, heart rhythm problems and even sudden death.

Feeding advice and medical measures prevent severe manifestations of the disease. They aim to avoid periods of fasting and to ensure adequate sugar intake at all times. These measures allow diagnosed children to develop normally.

Screening for MCAD deficiency will be implemented in France as of December 1, 2020. The estimated frequency is approximately 1/26,000 babies.

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>> ORPHA : 42

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>> Polak M, Cheillan D, Nguyen-Khoa T, Lachambre S, de Lonlay P, Arnoux JB, Courapied S, Khemiri A. Nouveautés dans le dépistage néonatal [New developments in neonatal screening]. Rev Prat. 2023 Dec;73(10):1119-1123. French. PMID: 38294483.

Another fatty acid beta-oxidation deficiency, Long-Chain 3-hydroxyacyl-CoA-Dehydrogenase deficiency (LCHADD), affects an average of one in every 100,000 newborns in Europe. The first symptoms appear between birth and the age of 2, when a young person or an infection is present. These conditions lead to metabolic decompensation, which can include hypoglycemia without ketosis, acidosis, hypotonia, neurological disorders that can even lead to coma, hepatocellular failure, cardiac rhythm disorders and rhabdomyolysis. Alongside these decompensations, chronic symptoms such as peripheral neuropathy, retinopathy and myopathy can appear from adolescence onwards. Treatment consists of introducing a diet with a very limited intake of long-chain fatty acids, and substituting them with medium-chain fatty acids. The child must eat regularly, and avoid fasting. To this end, nocturnal enteral nutrition may be proposed for certain children. Parents should be aware of the need for an emergency diet, which should be readily available to avoid decompensation.

Thanks to neonatal screening, the 10-year survival rate of sick children should rise from 14.3% (late diagnosis) to 65%.

>> ORPHA : 5

>> Polak M, Cheillan D, Nguyen-Khoa T, Lachambre S, de Lonlay P, Arnoux JB, Courapied S, Khemiri A. Nouveautés dans le dépistage néonatal [New developments in neonatal screening]. Rev Prat. 2023 Dec;73(10):1119-1123. French. PMID: 38294483.

Another deficiency in the beta-oxidation of fatty acids, primary systemic carnitine deficiency (Carnitine Uptake Deficiency, CUD) affects an average of one in 200,000 newborns in Europe. One of the steps in energy metabolism is the mitochondrial transfer of long-chain fatty acids, and carnitine enables this transfer via a specific transporter. Carnitine is therefore essential for the proper functioning of muscles, heart, kidneys and other organs. There are several clinical presentations of the disease:

– the infantile, metabolic form, between 3 months and 2 years of age: triggered by fasting or febrile episodes. Decompensation is accompanied by hypoglycemia without ketosis, coma with hyperammonemia, hepatic cytolysis and hepatomegaly. Seizures can lead to neurological sequelae in the form of delayed motor and cognitive development. Older children may present with progressive cardiomyopathy, with or without muscular weakness. If left untreated, events such as dyspnea, cerebral edema, convulsions and cardiac rhythm disorders can lead to coma and death.

– the cardiac form in children (aged 1 to 7): progressive heart failure with dilated cardiomyopathy, hypotonia, myolysis.

– the rare adult form: dilated cardiomyopathy, acute rhythm disorders, fatigability, myopathy. Clinical expression is highly variable, and may in some cases be totally asymptomatic. However, decompensation can occur at any time, and can be fatal (sudden death due to cardiac rhythm disorders).

Treatment consists of lifelong oral administration of L-carnitine (Levocarnil®). The prognosis is excellent as long as the patient remains on treatment. Stopping treatment within a few weeks leads to carnitine depletion in the body, which can lead to serious acute symptoms (heart rhythm disorders, sudden death).

>> ORPHA : 158

>> Polak M, Cheillan D, Nguyen-Khoa T, Lachambre S, de Lonlay P, Arnoux JB, Courapied S, Khemiri A. Nouveautés dans le dépistage néonatal [New developments in neonatal screening]. Rev Prat. 2023 Dec;73(10):1119-1123. French. PMID: 38294483.

Glutaryl-CoA dehydrogenase deficiency is an autosomal recessive neurometabolic disease. In Europe, it affects 1 in 100,000 newborns. It is due to mutations in the GCDH gene involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. The absence or inadequate functioning of the enzyme leads to the accumulation of glutaric and 3-hydroxyglutaric acids in the brain.

The « classic » infantile form (80-90% of cases) often begins between 3 and 36 months of age, abruptly, with acute neurological distress, most often occurring during a febrile or fasting episode. It leads to acute neurological signs, with the risk of severe disability (dystonia, psychomotor retardation, etc.), or even death.

Daily management of the disease includes a diet low in lysine and tryptophan, and carnitine supplementation, combined with an emergency protocol in the event of intercurrent illness to avoid acute neurological decompensation. The triggers for acute neurological decompensation should be known to the patient and family: fever, prolonged fasting, insufficient weight gain in infants, intercurrent pathology, etc. In these situations, it is important to increase energy intake (aiming for 120% of recommended daily intake), suppress protein intake for 24-48 hours, and double L-carnitine supplementation. Compliance with emergency treatment recommendations is imperative to prevent neuronal damage and the resulting secondary dystonia.

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>> ORPHA : 25

>> Polak M, Cheillan D, Nguyen-Khoa T, Lachambre S, de Lonlay P, Arnoux JB, Courapied S, Khemiri A. Nouveautés dans le dépistage néonatal [New developments in neonatal screening]. Rev Prat. 2023 Dec;73(10):1119-1123. French. PMID: 38294483.

Isovaleric acidemia (IVA) is an autosomal recessive disease caused by mutations in the IVD gene coding for the enzyme isovaleryl-CoA dehydrogenase, which affects leucine metabolism. In Europe, it affects around 1 in 100,000 newborns.

The disease is characterized by a variable clinical presentation, ranging from acute metabolic decompensation at neonatal onset to chronic non-specific manifestations at later onset, including developmental delay. All patients are subject to intermittent episodes of acute metabolic decompensation, characterized biologically by high urinary concentrations of isovaleric acid derivatives.

Acute neonatal presentation is characterized by the onset, within the first two weeks of life, of vomiting and a lethargic state progressing to coma. Biological tests reveal metabolic acidosis with increased anion gap, hyperammonemia and ketosis. If left untreated, the course can be fatal.

The disease can also become symptomatic later in life, with nonspecific signs such as developmental delay or intermittent episodes of drowsiness during intercurrent infections.

All patients are likely to develop recurrent episodes of acute decompensation. Episodes of acute metabolic decompensation are triggered by a prolonged period of fasting, or following increased dietary protein intake, or after an infection. They can be lethal in the absence of immediate treatment. The characteristic odor of isovaleric acid may be present (similar to the smell of sweaty feet). Severe developmental delay and neurological sequelae are observed in some patients.

Lifelong management, based on a protein-restricted diet, is required. Children diagnosed with VIA should be monitored by a physician and dietician specialized in hereditary metabolic diseases. Dietary supplements based on artificial proteins low in leucine may be necessary. L-carnitine and glycine may be prescribed to eliminate excess isovaleric acid. Emergency treatment in situations at risk of decompensation (infection, fasting, excess protein intake) is based on a high-calorie, protein-free diet. Protein intake should be stopped for no more than 3 days.

The prognosis for patients diagnosed during neonatal screening is excellent, and neurological development should be normal if diet and preventive measures are followed.

Symptomatic patients may retain significant neurological sequelae, such as delayed neurodevelopment, especially in cases of particularly severe acute metabolic decompensation.

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>> ORPHA : 33

>> Polak M, Cheillan D, Nguyen-Khoa T, Lachambre S, de Lonlay P, Arnoux JB, Courapied S, Khemiri A. Nouveautés dans le dépistage néonatal [New developments in neonatal screening]. Rev Prat. 2023 Dec;73(10):1119-1123. French. PMID: 38294483.

Hearing contributes to a child’s overall development, as do sight, touch, taste and smell. Hearing problems can be detected in the first days of a child’s life by means of a probe placed in the ear canal (Otoacoustic Emissions OAE) or with the help of a headset placed on the newborn’s ears (Auditory Evoked Potentials, AEP). The test is painless and harmless to the newborn. If an abnormality is detected, rapid and appropriate treatment is organized as soon as possible to avoid a delay in the development of communication that would hinder the child’s development.

>>https://relations-medicales.com/dnna-fipar-idf-2022/