# Diagnosis and management of congenital hypopituitarism in children

Sarah Castets, Julia Vergier, Rachel Reynaud, Cécile Thomas-Teinturier, Carine Villanueva, Jessica Amsellem, Régis Coutant, Pascal Barat, Gilles Brun, Emmanuel Bui Quoc, et al.

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Sarah Castets, Julia Vergier, Rachel Reynaud, Cécile Thomas-Teinturier, Carine Villanueva, et al. Diagnosis and management of congenital hypopituitarism in children. Archives de Pédiatrie, 2024, 31 (3), pp.165-171. 10.1016/j.arcped.2024.01.003. hal-04724565

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Practice guidelines

# Diagnosis and management of congenital hypopituitarism in children

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Sarah Castets<sup>a, *,</sup> Cécile Thomas-Teinturier<sup>b, c</sup>, Carine Villanueva<sup>d</sup>, Jessica Amsellem<sup>e</sup>, Pascal Barat<sup>f</sup>, Gilles Brun<sup>g</sup>, Emmanuel Bui Quoc<sup>h</sup>, Jean-Claude Carel<sup>i, m</sup>, Gian Paolo De Filippo<sup>j</sup>, Clara Kipnis<sup>i</sup>, Laetitia Martinerie<sup>j</sup>, Julia Vergier<sup>a</sup>, Alexandru Saveanu<sup>i, k</sup>, Natacha Teissier<sup>l</sup>, Régis Coutant<sup>e</sup>, Juliane Léger<sup>i, m</sup>, Rachel Reynaud<sup>a, k</sup>

ARTICLE INFO

**Article History:**
Received 18 October 2023
Revised 2 January 2024
Accepted 18 January 2024
Available online 27 March 2024

**Keywords:**
Pituitary deficiency
CPHD
Growth hormone deficiency
Diabetes insipidus

A B S T R A C T

Hypopituitarism (or pituitary deficiency) is a rare disease with an estimated prevalence of between 1/16,000 and 1/26,000 individuals, defined by insufficient production of one or several anterior pituitary hormones (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin), in association or not with diabetes insipidus (antidiuretic hormone [ADH] deficiency). While in adults hypopituitarism is mostly an acquired disease (tumors, irradiation), in children it is most often a congenital condition, due to abnormal pituitary development. Clinical symptoms vary considerably from isolated to combined deficiencies and between syndromic and non-syndromic forms. Early signs are non-specific but should not be overlooked. Diagnosis is based on a combination of clinical, laboratory (testing of all hormonal axes), imaging (brain magnetic resonance imaging [MRI] with thin slices centered on the hypothalamic–pituitary region), and genetic (next-generation sequencing of genes involved in pituitary development, array-based comparative genomic hybridization, and/or genomic analysis) findings. Early brain MRI is crucial in neonates or in cases of severe hormone deficiency for differential diagnosis and to inform syndrome workup. This article presents recommendations for hormone replacement therapy for each of the respective deficient axes. Lifelong follow-up with an endocrinologist is required, including in adulthood, with multidisciplinary management for patients with syndromic forms or comorbidities. Treatment objectives include alleviating symptoms, preventing comorbidities and acute complications, and optimal social and educational integration.

© 2024 The Authors. Published by Elsevier Masson SAS on behalf of French Society of Pediatrics. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/))

Introduction

Hypopituitarism is a chronic disease, caused by insufficient production or secretion of one or several anterior pituitary hormones (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic

hormone [ACTH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin), and more rarely, antidiuretic hormone (ADH), produced by the posterior pituitary. The prevalence of hypopituitarism is difficult to establish, but is estimated at between 1 in 16,000 and 1 in 26,000 individuals. Combined pituitary hormone deficiency (CPHD) in children is most often congenital, due to pituitary development abnormalities, which in some cases is associated with abnormal cerebral

<footnote><sup>a</sup>Assistance Publique Hôpitaux de Marseille, Hôpital la Timone, service de pédiatrie multidisciplinaire, Centre de Référence des Maladies Rares d'Origine Hypophysaire HYPO, Marseille, France</footnote>

<footnote><sup>b</sup>Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, Hôpital Bicêtre, service d'Endocrinologie et diabète de l'enfant, Le Kremlin Bicêtre, France</footnote>

<footnote><sup>c</sup>INSERM UMR 1018, Equipe d'épidémiologie des radiations, CESP, 94800 Villejuif, France</footnote>

<footnote><sup>d</sup>Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Service d'Endocrinologie Pédiatrique, Bron, France</footnote>

<footnote><sup>e</sup>CHU Angers, Service d'endocrinologie diabetologie pédiatrique, Angers, France</footnote>

<footnote><sup>f</sup>Centre hospitalier universitaire de Bordeaux, unite d'endocrinologie pédiatrique, Bordeaux, France</footnote>

<footnote><sup>g</sup>Hôpital Européen, neuroradiologie, Marseille, France</footnote>

<footnote><sup>h</sup>Assistance Publique-Hôpitaux de Paris, Hôpital universitaire Robert Debré, service d'ophtalmologie, Paris, France</footnote>

<footnote><sup>i</sup>Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Hôpital universitaire Robert Debré, service d'Endocrinologie et Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes de la Croissance et du Développement, Paris, France</footnote>

<footnote><sup>j</sup>Assistance Publique Hôpitaux de Marseille, Hôpital Conception, laboratoire de biologie moléculaire, Centre de Référence des Maladies Rares d'Origine Hypophysaire HYPO, Marseille, France</footnote>

<footnote><sup>k</sup>Aix Marseille Université, INSERM, MMG, U 1251, Marseille, France</footnote>

<footnote><sup>l</sup>Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Hôpital universitaire Robert Debré, service de Chirurgie ORL et cervico-faciale pédiatrique, Paris, France</footnote>

<footnote><sup>m</sup>Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1141, Paris, France</footnote>

<footnote>* Corresponding author.
E-mail address: sarah.castets@ap-hm.fr (S. Castets).</footnote>
development. Congenital hypopituitarism can be syndromic or non-syndromic. Early diagnosis is important and the associated comorbidities and risk of complications and decompensation mean that long-term specialist, often multidisciplinary, follow-up is required.

## Methods

These guidelines were established following the French Health Authority (Haute Autorité de Santé) 2012 instructions for preparing national diagnosis and treatment guidelines for rare diseases (Méthode d'élaboration d'un protocole national de diagnostic et de soins pour les maladies rares; available online at www.has-sante.fr). The guidelines were established by a group of specialists from across France based on the literature, which were then reviewed, edited, and discussed by a group of reviewers. This article is a summary of the committee's recommendations for pediatric patients (Fig. 1).

## Diagnosis and initial workup

Clinical presentations of congenital hypopituitarism vary widely depending on the nature of the deficiency (isolated deficiency or CPHD), and the association or not with syndromic forms.

The age at diagnosis ranges from the neonatal period to (in rare cases) adulthood. Hypopituitarism is diagnosed earlier in patients with CPHD or syndromic disease. The first clinical signs are often non-specific [1] but should not be overlooked: Their unexplained presence in neonates or children should prompt an assessment of pituitary function or first-line brain magnetic resonance imaging (MRI) to investigate pituitary development abnormalities.

### Initial clinical signs

#### Clinical signs of hypopituitarism

The clinical signs of hypopituitarism are listed in Table 1.

### Extra-pituitary clinical signs that should prompt an evaluation of pituitary function

The first signs can be extra-pituitary and may involve abnormalities of brain development (holoprosencephaly, septo-optic or corpus callosum dysplasia) [2], craniofacial development (orofacial cleft, solitary median maxillary central incisor or lateral incisor agenesis, pyriform aperture stenosis, choanal atresia), or eye development (microphthalmia, anophthalmia, retinitis, coloboma of the iris or retina) [3], depending on the underlying mechanism and the timing

<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Process of establishing recommendations for pediatric patients. Abbreviations: TSH: thyroid-stimulating hormone; ACTH: adrenocorticotropic hormone.</figcaption></figure>
<table><caption>**Table 1**
Clinical signs of hypopituitarism at different ages.</caption><thead><tr><th></th><th>Neonatal period</th><th>Childhood</th><th>Adolescence</th></tr></thead><tbody><tr><td><strong>Somatotropic deficiency</strong> [5,7]</td><td><ul><li>Hypoglycemia</li><li>Micropenis</li><li>Normal or near-normal (−1 SDS) birth length</li></ul></td><td><ul><li>Short stature with:<ul><li>Growth rate &lt; −1 SDS leading to more than 0.5 SDS drop in growth profile over 1 year</li><li>Height &lt; −1.5 SDS of midparental height</li><li>Height &lt; −2 SDS</li></ul></li><li>No increase in height gain in the presence of excessive weight gain</li></ul></td><td></td></tr><tr><td><strong>Thyrotropic deficiency</strong> [8]</td><td><ul><li>Hypotonia</li><li>Prolonged jaundice</li><li>Hypothermia</li><li>Decreased activity</li><li>Feeding difficulties</li><li>Myxedema</li><li>Macroglossia</li><li>Lack of goiter</li></ul><p>Note: signs often weak or absent at birth.</p></td><td><ul><li>Short stature</li><li>Overweight</li><li>Weakness</li><li>Slowness</li><li>Constipation</li><li>Neurodevelopmental disorders.</li></ul><p>Note: clinical signs are more moderate than in primary thyroid deficiency.</p></td><td></td></tr><tr><td><strong>Corticotropic deficiency</strong> [22]</td><td><ul><li>Recurrent hypoglycemia without hyperinsulinism</li><li>Prolonged jaundice</li><li>Dilutional hyponatremia (without hyperkalemia)</li><li>Family history of perinatal mortality</li></ul></td><td><ul><li>Weakness</li><li>Low physical endurance</li><li>Hypoglycemia symptoms</li><li>Hyponatremia without hyperkalemia</li></ul></td><td></td></tr><tr><td><strong>Gonadotropic deficiency</strong> [11]</td><td><ul><li>In boys, micropenis and/or bilateral cryptorchidism and/or small testicular volume</li><li>Hypospadias (exceptional)</li><li>In girls, no early signs</li></ul><p>NB: associated anosmia strongly indicative of Kallman syndrome</p></td><td></td><td><ul><li>Pubertal delay</li></ul></td></tr><tr><td><strong>Diabetes insipidus</strong> [12,23]</td><td><ul><li>Polyuria (&gt; 150 mL/kg/day) from 2 to 3 weeks of age</li><li>No weight gain</li><li>Dehydration</li><li>Hypernatremia, hemoconcentration</li><li>Unexplained fever</li></ul></td><td><ul><li>Polyuria<ul><li>&gt; 100–110 mL/kg/day until 2 years</li><li>&gt; 40–50 mL/kg/day in older children (&gt; 2 L/m²/day)</li></ul></li><li>Polydipsia</li></ul></td><td></td></tr></tbody></table>

SDS: standard deviation score.

during ontogeny. Other malformations are also possible, such as skeletal abnormalities (polydactyly), vertebral anomalies (short neck with limited head and neck rotation), and much more rarely heart, kidney and gastrointestinal abnormalities as well as neurosensory (vision or hearing) [3] and/or neurodevelopmental disorders [4] of varying severity. These associations sometimes appear together as part of a midline syndrome. Finally, hypopituitarism can be a symptom of various syndromes such as CHARGE, Fanconi, Rieger, and Pallister-Hall syndromes.

## Diagnostic approach

The diagnosis of hypopituitarism should be based on a combination of clinical, laboratory, imaging, and in some cases genetic findings.

### Laboratory tests

The particular variations of hormonal secretion rates in the first weeks of life (no circadian rhythm, adaptive processes) make laboratory findings difficult to interpret. These should therefore be analyzed by pediatric endocrinologists. In cases of suspected hypopituitarism, all hormone-producing cell types should be evaluated.

**Somatotropic deficiency.** In the neonatal period. Secretion stimulation tests are inappropriate or contraindicated before the age of 6 months [5]. The diagnosis should be based on a combination of findings: recurrent hypoglycemia (the absence of which does not rule out the diagnosis), presence of other deficiencies, low levels of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3; more informative than IGF1 at that age) (normal levels do not rule out the diagnosis), and low baseline GH level (<5 ng/mL) in the first 7 days of life [5]. Absence of an increase in GH during spontaneous hypoglycemia is poorly specific and is not a good diagnostic criterion [6].

**In children and adolescents.** In patients with short stature, a diagnosis of GH deficiency can be made if peak GH secretion is below

7 ng/mL (20 mUI/L) [7] in two separate stimulation tests (including at least one test with two combined stimuli), with an IGF-1 level < −1 standard deviation score (SDS). A single test is sufficient if the patient has another hormone deficiency or pituitary abnormality on MRI.

**Thyrotropic deficiency.** The diagnosis is confirmed by reduced free T4 and free T3 levels, with no substantial increase in TSH (compared with age- and test-specific reference values) [8]. Hypothalamic abnormalities can lead to moderately increased TSH levels. The differential diagnoses to exclude are transient hypothyroxinemia of prematurity, low T3 and T4 syndrome in patients with severe disease, and treatments that inhibit the thyrotropic axis (dopamine, corticosteroids, caffeine, etc.) and can thereby mimic congenital thyrotropic deficiency [8].

**Corticotropic deficiency.** In the neonatal period. The absence of circadian rhythm in the first few months of life makes diagnosis difficult, and may lead to overdiagnosis, since cortisol levels can be physiologically low in newborns. Low cortisol during spontaneous hypoglycemia is poorly specific and is not a good diagnostic criterion [9]. Isolated corticotropic deficiencies are very rare; in most cases, the deficiency is one of several in CPHD. The diagnosis should be based on multiple measurements (at different times of day) of cortisol and ACTH levels, and possibly a Synacthen test [10].

**In children and adolescents.** The diagnosis is established by low blood cortisol levels between 7 and 9 a.m. and/or during a stimulation test, with non-elevated ACTH. Differences in measurement methods for cortisol levels mean that threshold levels vary. In general, however, a cortisol level above 140 ng/mL between 7 and 9 a.m. makes a diagnosis of adrenal deficiency unlikely, while a result below 40 ng/mL makes the diagnosis of adrenal deficiency very likely. Cortisol levels between 40 and 140 ng/mL require stimulation tests to be interpreted in the case of clinical suspicion [10].

**Gonadotropic deficiency.** Gonadotropic deficiency can be identified during minipuberty or during adolescence. Physiological minipuberty
corresponds to the transient postnatal activation of the gonadotropic axis from 15 days to 3 months of life in boys, and for slightly longer in girls. Minipuberty may be important for future fertility in boys but its role in girls is yet to be determined.

*In the neonatal period.* In boys, gonadotropic deficiency should be suspected if testosterone and anti-müllerian hormone (AMH) levels are low (<1 ng/mL and <200 pmol/L, respectively) during the first 3 days of life (LH and FSH levels being uninformative at this age). The diagnosis is then confirmed by the absence of LH, FSH, testosterone, AMH, and inhibin B elevation during minipuberty. In girls, the diagnosis is based on the absence of LH and FSH elevation during minipuberty [11].

*In adolescents*, the laboratory profiles are as follows [11]:

* In boys with a bone age greater than 13 years: low testosterone levels without stimulated or basal elevation of LH and FSH. Inhibin B levels are most often low.

* In girls with a bone age greater than 11 years: low estradiol without stimulated or basal elevation of LH and FSH. The sensitivity of estradiol measurements is low in early puberty.

*Central diabetes insipidus.* Congenital diabetes insipidus is very rare and is generally associated with severe midline defects or septo-optic dysplasia. It is defined by hypotonic polyuria with plasma hypertonicity: urine/plasma osmolarity ratio <1, plasma osmolality >300 mosm/L, hypernatremia >145 nmol/L, and hemoconcentration [12]. Hemoconcentration and hypernatremia may, however, be absent under complete fluid compensation of the polyuria. In partial forms (urinary osmolality between 300 and 800 mOsmol/kg), a water deprivation test may be considered if there is no anterior pituitary defect and brain and pituitary MRI findings are normal. Water deprivation tests are strictly contraindicated in neonates and infants. ADH measurements are of little value but copeptin concentrations (copeptin is a cleavage product of pre-pro-ADH) can be informative: In children, copeptin levels <2.2 pmol/L in the context of polyuria with plasma hyperosmolality are strongly indicative of central diabetes insipidus [13]; in neonates older than 3 days, copeptin levels below 8 pmol/L support the diagnosis of central diabetes insipidus [14].

## Imaging

The imaging workup should include high-resolution T1- and T2-weighted MRI, including thin (2–3 mm) slices centered on the hypothalamic–pituitary region, along with whole-brain and olfactory bulb analysis. High-resolution 3D gradient echo images with T2 FIESTA weighting are commonly used to detect pituitary stalk malformations.

The MRI appearance of the pituitary region in the neonatal period is specific, with stronger T1 signal than in infants or adults, increased pituitary height (4–5 mm), and a bulging appearance. The physiological T1 hyperintensity of the posterior pituitary appears progressively in the first 2 months of life but is absent in 10 % of healthy individuals. Its absence is not always indicative of central diabetes insipidus.

Congenital pituitary deficiencies are associated with malformations of the hypothalamic–pituitary region in 50%–100% of cases of CPHD, and more rarely in isolated congenital GH deficiency [15]. These abnormalities include (a) hypoplastic pituitary (<3 mm); (b) ectopic posterior pituitary associated or not with pituitary stalk interruption syndrome (thin [<1 mm] or interrupted pituitary stalk with or without aplasia or hypoplasia of the anterior pituitary); (c) increased pituitary volume with homogeneous contrast enhancement; (d) empty sella turcica; (f) septo-optic dysplasia, defined by at least two of the following defects: optic nerve hypoplasia, midline brain abnormalities (absence of the septum pellucidum and/or corpus callosum agenesis), and hypopituitarism. There may also be other associated intracranial abnormalities, such as agenesis of the olfactory bulbs and/or of the

olfactory tract, holoprosencephaly, schizencephaly, heterotopia, Chiari malformation, cerebellar malformation, persistent hypophyseal canal, microphthalmia, and hypothalamic hamartoma.

Identification of a structural abnormality of the hypothalamic–pituitary region, and/or of the brain, optic, or olfactory structures, provides strong diagnostic and etiological evidence. However, normal MRI findings do not rule out the diagnosis of hypopituitarism.

## Genetic diagnosis

More than 30 genes have been implicated in pituitary deficiencies, whether isolated or combined, syndromic or not [3,16]. Outside specific syndromic forms or a documented family history, the recommendation is to offer genetic analysis to the index case by next-generation sequencing (NGS) of a panel of the most relevant genes. This can be completed or preceded by array comparative genomic hybridization (CGH) analysis, particularly in syndromic forms. If all results are negative, further investigations are possible by whole-genome sequencing of the patient and their parents.

## Identifying comorbidities

A systematic investigation of potential extra-pituitary abnormalities is required for patients with CPHD or syndromic disease because of possible malformations associated with developmental abnormalities of the hypothalamic–pituitary region or distant regions during embryogenesis.

## Neurological and neurocognitive comorbidities

Neurodevelopmental disorders occur mostly when brain abnormalities are observed on MRI [4]. Families should be informed of the increased risk of brain malformations, neurodevelopmental delays, and more severe or less severe learning difficulties. Epilepsy is rare.

## Ophthalmic comorbidities

Ophthalmic defects are present in 10%–20% of cases and are highly variable [3]. Coloboma is a closure abnormality that can affect the iris, lens, choroid, optic disc, macula, and the optic nerve. It is sometimes associated with microphthalmia and severe forms can lead to functional impairment. Vision is compromised if the optic nerve is affected. Nystagmus can be a symptom of bilateral vision impairment (severe bilateral coloboma, optic nerve hypoplasia) or of an oculomotor abnormality. Early diagnosis of these abnormalities is crucial to preserve vision in these patients.

## Oral and maxillofacial comorbidities

Various craniofacial midline defects may be present as frontal bossing, hypertelorism, midface hypoplasia (saddle nose of varying severity, nasal defects, choanal stenosis or atresia, pyriform aperture stenosis), orofacial cleft, palate defect, dental agenesis, median maxillary central incisor, anteverted helix, deep philtrum and thin upper lip, and small chin. Soft palate cleft may affect speech quality. Orthodontic treatment is often necessary in patients with maxillary hypoplasia or dental malocclusion. Congenital hypopituitarism may also be associated with deafness [3].

## Other associated defects

The presence of associated defects can help identify a syndromic form such as CHARGE syndrome (cardiopathy, deafness, hemivertebrae etc.), Kallmann syndrome (anosmia, renal hypoplasia in boys), Webb–Dattani syndrome (hydronephrosis), or Culler–Jones syndrome (postaxial polydactyly). These diagnoses should lead to specific genetic analyses and follow-up in a tertiary referral center.

## Hypothalamic dysfunction

Hypothalamic dysfunction should be suspected in patients with early and rapidly progressing obesity because of satiety disorder and
an abnormal basal metabolic rate, hypothalamic adipsia with neuro-
genic hypernatremia, neurovegetative respiratory or thermal regula-
tion disorders, or behavioral disorders.

Treatment strategies

The treatment and follow-up of patients with hypopituitarism
should be explained and managed by pediatric endocrinologists in a
tertiary hospital. The objectives of treatment are the alleviation of
symptoms and the prevention of complications.

Hormone replacement

Somatotropic deficiency

The main objective in neonates and infants is to prevent hypoglycemia, and in children to achieve catch-up growth. The recommended GH dose is 25–35 µg/kg/day, administered either daily as soon as the diagnosis is known or weekly (from the age of 3 years), subcutaneously and with doses adjusted to the clinical response and IGF-1 levels [7]. In neonates and in infancy in the case of hypoglycemia, GH replacement is a medical emergency and we recommend the highest of the recommended dose.

Thyrotropic deficiency

Central hypothyroidism is treated with oral levothyroxine. In the neonatal period, patients with severe hypothyroidism (free T4 <5 pmol/L) should receive 8–10 µg/kg/day (oral solution) and patients with less severe hypothyroidism, 5–7 µg/kg/day in a single daily dose. In children and adolescents, doses can be reduced to, respectively, 3–5 and 2–2.4 µg/kg/day [8].

Gonadotropic deficiency

In the neonatal period. In boys, recombinant androgen or gonado-
tropin therapy is today proposed during minipuberty to promote
penile growth and testicular descent. On its own, gonadotropin ther-
apy increases testicular volume and may facilitate later fertility under
treatment [17].

Puberty induction leads to the appearance of secondary sexual
characteristics, a growth spurt, and bone and muscle development. It
also has social, psychological, and sexual effects and must be per-
formed at a physiological age (from 11 years in girls and 12–13 years
in boys) if hypopituitarism has been previously diagnosed. In girls,
treatment involves oral or transdermal 17-beta-estradiol (natural
estrogen), initially at low doses that should gradually be increased
over 2–3 years, then in sequential association with a progestogen
[11]. In boys, two treatment options can be proposed [11]: (1) gonad-
otropin pulses several times a week either by subcutaneous injection
or via GnRH pump — this treatment leads to virilization, testicular
growth, and eventually spermatogenesis; or (2) intramuscular testos-
terone injections, with doses increased over 3 years up to an adult
dose (250 mg/month), which leads to virilization without testicular
growth or spermatogenesis.

Corticotropic deficiency

The two objectives of hydrocortisone replacement are: (1) correctig the corticotropic deficiency, avoiding acute adrenal insufficien cy, and (2) optimizing patient quality of life by preventing fatigue. Follow-up is important to avoid chronic overdose, which can increase morbimortality, and underdosing, which can lead to acute adrenal insufficiency. The recommended doses for hydrocortisone replacement are 8–10 mg/m²/day in children and 15 mg/m²/day in infants, in two to three daily oral doses [10]. In neonates, hydrocortisone replacement is a medical emergency.

Diabetes insipidus

Central diabetes insipidus is often well tolerated if patients have free access to fluids and thirst is preserved. If not, rapid dehydration is a major risk. Treatment involves desmopressin [18], most often administered as an oral lyophilizate (scored, dilutable tablet) but also available as a nasal spray or as an injectable solution (for IV, IM, or SC injection). Treatment should be initiated at low doses (1–2 µg/kg/day) and then adapted under careful monitoring of diuresis, weight, and sodium levels. Overdosing carries a risk of water intoxication, particularly in neonates and infants because of their exclusively liq- uid diet and low urine concentrating ability. Desmopressin treatment at this age is therefore a delicate choice and should be discussed in a specialist treatment center.

Managing emergencies

Acute adrenal insufficiency

In acute adrenal insufficiency, treatment should be initiated on suspicion alone, without waiting for laboratory confirmation [10]. Hydrocortisone hemisuccinate should be administered parenterally (by IV, IM, or SC injection) at 1–2 mg/kg every 6–8 h, with intravenous fluids, followed by intravenous dextrose saline (150–180 mL/kg/day in neonates, 2.5–3 L/m²/day in children, with 10–15 mEq/kg/day, maximum 400 mEq NaCl). This treatment should be adapted based on close monitoring of the patient's glucose and sodium levels. Oral hydrocortisone should be restarted at three times the usual dose, after stabilization and return to oral feeding, in three daily doses, then gradually reduced to the normal dose over a few days.

Hydrocortisone doses should be increased to 30 mg/m²/day in three to four daily doses during intercurrent illness to prevent acute adrenal insufficiency [10]. In the absence of clinical improvement or if oral administration is impossible, IM or SC hydrocortisone hemisuccinate should be administered before hospitalization by a health-care professional, the patient themselves, or a family member: 25 mg in children younger than 1 year, 50 mg in children aged 1–6 years, and 50 mg in children older than 6 years followed by an additional 50 mg after 15 min, if required (if clinical signs of acute adrenal insufficiency persist).

Following major surgery, the same protocol is recommended as
for acute adrenal crisis until return to oral feeding, followed by three
times the usual oral dose in three daily doses, and then a gradual
reduction down to the usual doses over a few days. In the case of
minor surgery with mild anesthesia, for tests that require fasting, or
during acute illness preventing oral hydrocortisone use, the proposed
treatment is IV hydrocortisone at 1 mg/kg every 6–8 h or 1 mg/kg IM
hydrocortisone every 6–8 h until return to oral feeding, not exceed-
ing 25 mg/6 h. Oral hydrocortisone doses should then be tripled and
spread over three daily doses for a few days.

Patient education

Patient education can improve disease knowledge, treatment
compliance, management of emergencies, and the overall quality of
life of children and their families. Patients and their families should
be offered educational resources wherever possible.

Follow-up

Monitoring of hormonal supplementation

Regular follow-up with a pediatric endocrinologist is required, on a monthly basis in infancy, then quarterly to half-yearly in children and adolescents.
### Somatotropic deficiency

The main parameter to monitor is height growth. In neonates and infants, the major focus should be on preventing hypoglycemia. The laboratory parameter to monitor is IGF-1, with a target range of 0–2 SDS, avoiding values below –2 or above +2 SDS. Treatment is usually continued until the latter part of the growth period, defined by a bone age of 14–15 years in girls and 16–17 years in boys, or by a growth rate of <3 cm/year [7]. In adolescents, treatment can be continued at the end of the growth period, notably to support bone metabolism. The deficiency should be reevaluated after stopping treatment, which should then be reintroduced if the deficiency persists, for metabolic and physiological reasons. Potential adverse effects should be explained and investigated during follow-up (glucose intolerance, benign intracranial hypertension, proximal femoral epiphysiolysis, worsening scoliosis).

### Thyrotropic deficiency

Monitoring essentially involves measuring free T4 levels, with target values in the upper part of the normal range. Routine TSH measurements are not indicated.

### Corticotropic deficiency

The absence of laboratory markers means that doses have to be adapted based on clinical signs of hydrocortisone over- or underdose, which have to be investigated at each follow-up visit and taught to families. Chronic overdose leads to drug-induced Cushing syndrome (overweight, slowing of height and pubertal growth) and increases the risk of metabolic and cardiovascular disease. Underdosing leads to symptoms of adrenal insufficiency (fatigue, anorexia, weight loss) and increases the risk of acute adrenal insufficiency [10].

### Gonadotropic deficiency

Pubertal development should be monitored every semester through sexual maturity rating (Tanner staging), measurement of the growth rate and bone age, and for boys, a laboratory workup [11], including testosterone levels and a complete blood count (polycythemia in the case of overdose).

### Central diabetes insipidus

The aim is to achieve fluid balance with normal diuresis. Patients should learn to defer or avoid taking desmopressin in the case of anuria between two desmopressin doses, and to bring forward or add a dose in the case of polyuria. Patients should be allowed to drink according to thirst, but fluid intake should be quantified in those with a hypothalamic disorder. Follow-up should be based on diuresis, weight, and sodium levels, which should be measured every 6 months at least.

Patients and/or their parents should be made aware of two emergency situations: (1) water intoxication, the signs of which (headache, nausea, weight gain, confusion, convulsions) should lead to cessation of desmopressin and fluid intake and to medical consultation; and (2) dehydration and the associated risk factors (fever, diarrhea, hot weather), which should be managed by adapting desmopressin doses or by consulting a doctor.

### Monitoring of other hormonal axes

Deficiencies may already be present at diagnosis or appear subsequently. Regular clinical and laboratory monitoring of all axes is therefore essential until adulthood. Screening for other deficiencies can in some cases be guided, if known, by the underlying genetic cause.

### Screening for complications

#### Neurocognitive complications

Neurocognitive complications may occur depending on the severity of the patient's condition and the time to diagnosis, the number of severe and/or repeated hypoglycemic events in early childhood, prolonged severe hypothyroidism, and on potentially associated malformations. Early psychomotor development, then school achievement, should be evaluated at each follow-up visit, and a neuropsychological assessment should be proposed from the age of 4 or 5 years for patients with learning disabilities.

#### Visual complications

An ophthalmological assessment with fundus examination must systematically be performed at diagnosis, then again at 12–15 months of age, and between 3 and 4 years of age at least in the case of early diagnosis.

#### Metabolic and cardiovascular complications

Combined pituitary hormone deficiency is known to increase the risk of cardiovascular and metabolic disease (metabolic syndrome, cerebrovascular events), particularly in the case of insufficient substitution [19].

#### Bone complications

Loss of bone mass is common in patients with hypopituitarism. Adequacy of calcium and vitamin D intake should be monitored in adolescents and bone density should be evaluated by osteodensitometry at the end of childhood.

#### Transition to adult care

Parents of patients with CPHD should be informed at an early stage of the need to continue hormone replacement therapy into adulthood to preserve optimal body composition, quality of life, and to avoid comorbidities associated with hormone deficiency. Somatotropic hormone function should be reevaluated at the end of the growth period in patients with somatotropic deficiency, including in those with ectopic posterior pituitary (potentially reversible GH deficiency). However, reevaluation is unnecessary in the following cases [20]: severe congenital CPHD (involving ≥3 pituitary cell lines), and hypopituitarism with a known genetic cause and/or due to a cerebral or craniofacial midline defect. The gonadotropic axis should be reevaluated at the end of puberty in the case of isolated deficiency, after cessation of sex steroid treatment for 1–3 months, because some cases of isolated gonadotropic deficiency are reversible [21].

#### Patient support

#### Psychological management

Psychological support is often required at various stages depending on the individual patient needs. The psychological wellbeing of the patient's families should also be carefully monitored.

#### Patient associations

All healthcare workers and patients should be informed of the existence of patient associations for these conditions. In rare diseases, these associations allow patients to connect with others, share information and experiences, and come to terms with their condition. They can contribute to improving patient care pathways by promoting recognized care networks.

### Conclusion

Presentations of congenital hypopituitarism are highly variable (ranging from isolated hormone deficiency to CPHD, with syndromic
and non-syndromic forms). The diagnosis should readily be consid-
ered based on often non-specific clinical signs, and can be confirmed
by a combination of findings after referral to a pediatric endocrinolo-
gist. Genetic analyses (gene panel NGS and/or array CGH and/or
genomic analysis) are an important part of patient care. Treatment is
based on age-adapted hormone replacement and on patient/family
education, focusing among others on preventing and managing adre-
nal insufficiency.

Funding

The preparation of national diagnosis and treatment guidelines for
congenital hypopituitarism was funded by the French government
(*Direction Générale de l'Offre de Soins* 2019). This article is based on
the guidelines published on the French Health Authority (HAS) web-
site on 1 December 2021.

**Declaration of competing interest**

None.

Acknowledgments

The authors thank the reviewers of the pediatric part of the
French national diagnosis and treatment guidelines for congenital
hypopituitarism (Prof. B. Chabrol, Prof. I. Netchine, Prof. M. Nicolino,
Prof. M. Tauber), and Paul Guerry (Green Grow Scientific) for translat-
ing the article.

References

[1] Bosch I Ara L, Katugampola H, Dattani MT. Congenital hypopituitarism during the neonatal period: epidemiology, pathogenesis, therapeutic options, and outcome. *Front Pediatr* 2020;8:600962.

[2] Cameron FJ, Khadilkar VV, Stanhope R. Pituitary dysfunction, morbidity and mortality with congenital midline malformation of the cerebrum. Eur J Pediatr 1999;158:97-102.

[3] Jullien N, Saveanu A, Vergier J, et al. Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort. Clin Endocrinol 2021;94:277-89.

[4] Garcia-Filion P, Epport K, Nelson M, et al. Neuroradiographic, endocrinologic, and ophthalmic correlates of adverse developmental outcomes in children with optic nerve hypoplasia: a prospective study. Pediatrics 2008;121:e653-9.

[5] Binder G, Weidenkeller M, Blumenstock G, et al. Rational approach to the diagnosis of severe growth hormone deficiency in the newborn. J Clin Endocrinol Metab 2010;95:2219-26.

[6] Hussain K, Hindmarsh P, Aynsley-Green A. Spontaneous hypoglycemia in child-hood is accompanied by paradoxically low serum growth hormone and appropriate cortisol counterregulatory hormonal responses. J Clin Endocrinol Metab 2003;88:3715-23.

[7] Grimberg A, DiVall SA, Polychronakos C, et al. Guidelines for growth hormone and insulin-like growth factor-i treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Horm Res Paediatr 2016;86:361-97.

[8] Persani L, Brabant G, Dattani M, et al. 2018 European Thyroid Association (ETA) guidelines on the diagnosis and management of central hypothyroidism. Eur Thyroid J 2018;7:225-37.

[9] Kelly A, Tang R, Becker S, et al. Poor specificity of low growth hormone and corti-sol levels during fasting hypoglycemia for the diagnoses of growth hormone defi-ciency and adrenal insufficiency. Pediatrics 2008;122:e522-8.

[10] Reznik Y, Barat P, Bertherat J, et al. SFE/SFEDP adrenal insufficiency French consensus: introduction and handbook. Ann Endocrinol 2018;79:1-22.

[11] Boehm U, Bouloux PM, Dattani MT, et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 2015;11:547-64.

[12] Djermane A, Elmaleh M, Simon D, et al. Central diabetes insipidus in infancy with or without hypothalamic adipsic hypernatremia syndrome: early identification and outcome. J Clin Endocrinol Metab 2016;101:635-43.

[13] Tuli G, Tessaris D, Einaudi S, et al. Copeptin role in polyuria-polydipsia syndrome differential diagnosis and reference range in paediatric age. Clin Endocrinol 2018;88:873-9.

[14] Evers KS, Wellmann S. Arginine vasopressin and copeptin in perinatology. Front Pediatr. 2016;4:75.

[15] Pampanini V, Pedicelli S, Gubinelli J, et al. Brain magnetic resonance imaging as first-line investigation for growth hormone deficiency diagnosis in early childhood. Horm Res Paediatr 2015;84:323-30.

[16] Fang Q, George AS, Brinkmeier ML, et al. Genetics of combined pituitary hormone deficiency: roadmap into the genome era. Endocr Rev 2016;37:636-75.

[17] Bouvattier C, Maione L, Bouligand J, et al. Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism. Nat Rev Endocrinol 2011;8: 172-82.

[18] Ooi HL, Maguire AM, Ambler GR. Desmopressin administration in children with central diabetes insipidus: a retrospective review. J Pediatr Endocrinol Metab JPEM 2013;26:1047-52.

[19] Abe SY, Dos Santos KS, Barbosa BFB, et al. Metabolic syndrome and its components in adult hypopituitary patients. Pituitary 2020;23:409-16.

[20] Juul A, Kastrup KW, Pedersen SA, et al. Growth hormone (GH) provocative retesting of 108 young adults with childhood-onset GH deficiency and the diagnostic value of insulin-like growth factor I (IGF-I) and IGF-binding protein-3. J Clin Endocrinol Metab 1997;82:1195-201.

[21] Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007;357:863-73.

[22] Couture C, Saveanu A, Barlier A, et al. Phenotypic homogeneity and genotypic variability in a large series of congenital isolated ACTH-deficiency patients with TPIT gene mutations. J Clin Endocrinol Metab 2012;97:E486-95.

[23] Di Iorgi N, Napoli F, Allegri AEM, et al. Diabetes insipidus–diagnosis and management. Horm Res Paediatr 2012;77:69–84.