Congenital Combined Hypopituitarism

Class of disorders of anterior pituitary development and differentiation, defined by growth hormone deficiency associated with at least one other anterior pituitary deficiency, with more than thirty genes implicated (POU1F1, PROP1, LHX3, LHX4, HESX1, OTX2, RNPC3, ROBO1, SOX3, GLI2, FOXA2, EIF2S3, NFKB2, KCNQ1 and others), deficiencies that develop progressively and a molecular cause identified in a minority of patients.

Literature and regulatory information updated: 26 October 2026.

0. Initial Reference Table

0.1. Class profile

0.2. Entities of the class: identifiers

AR: autosomal recessive; AD: autosomal dominant. OMIM numbers, titles, inheritance and cytobands as in the entries consulted on 26/10/2026; the cytobands of NFKB2 and KCNQ1 are those recorded in GeneGuidance [2, 3, 5, 10, 11, 14, 28–40].

0.3. Clinical summary by main entity

IGHD: isolated GH deficiency; CNV: copy number variation; PSIS: pituitary stalk interruption syndrome.

1. Introduction

1.1. Historical overview

The genetics of congenital hypopituitarism began with murine models of dwarfism. In 1990, Li and colleagues showed that Snell and Jackson dwarf mice carried variants in both alleles of the gene for the POU transcription factor Pit-1, with loss of GH, PRL and TSH expression and hypoplasia of the three corresponding cell lineages; this was the first direct link between a transcription factor and organogenesis in a mammal [52]. In 1992, three studies transposed the model to humans: Tatsumi and colleagues described a patient with cretinism and combined TSH, GH and PRL deficiency due to homozygosity for a nonsense variant of PIT1 (now POU1F1), the first human defect of a transcriptional activator with deficiency of several target genes [53]; Radovick and colleagues identified a heterozygous variant in the POU homeodomain whose protein bound deoxyribonucleic acid (DNA) normally but acted as a dominant inhibitor, the first description of the dominant-negative mechanism in this class [54]; and Pfäffle and colleagues described two Dutch families with an alanine-to-proline substitution in the POU-specific domain and GH, PRL and TSH deficiency without pituitary hypoplasia [55].

In 1998, Wu and colleagues positionally cloned the Prop1 gene of the Ames (df) mouse, epistatic to the Snell and Jackson mice, and found inactivating PROP1 variants in the homozygous or compound heterozygous state in four families with CPHD; unlike patients with POU1F1 variants, these patients did not produce sufficient LH and FSH and did not enter puberty spontaneously, and PROP1 came to be considered a major cause of human CPHD [56]. In the same year, Dattani and colleagues showed that Hesx1-null mice had anterior forebrain defects and pituitary dysplasia comparable to septo-optic dysplasia and identified two siblings homozygous for an arginine-to-cysteine substitution in the HESX1 homeodomain [57]. Hanhart studied, in 1925 and 1953, familial dwarfism in inbred populations of Switzerland and of the island of Krk (Veglia), and the multiple cases among the Hutterites of the USA and Canada, described in 1967, indicated recessive inheritance of panhypopituitarism; in 2002 they were confirmed to be due to PROP1 c.301_302del [6]. Culler and Jones described in 1984 a boy with hypopituitarism and bilateral postaxial polydactyly whose father and brother had polydactyly only, the family in which the first truncating GLI2 variant was later identified [13]. The Croatian island of Krk provided, in 1999, the molecular explanation for an isolated population of “little people” described decades earlier: the PROP1 variant c.150del [58]. LHX3 followed in 2000, with deficiency of all anterior pituitary hormones except ACTH and a rigid cervical spine in two consanguineous families [45], and LHX4 in 2001, with a splice variant segregating dominantly over three generations with pituitary, hindbrain and sella turcica defects [59].

The second generation of genes came from exome sequencing. In 2017, ROBO1 was associated with pituitary stalk interruption syndrome (PSIS) in five heterozygous cases, with incomplete penetrance and ocular anomalies [51], and KCNQ1 was associated with maternally transmitted GH deficiency with gingival fibromatosis in three families [32]. In 2019 the first recessive form of ROBO1 was described [60]; in 2022, a series of 15 patients from 9 families established RNPC3, a component of the minor spliceosome, as a cause of severe GH deficiency with hypoprolactinaemia and primary ovarian insufficiency [61]. In 2024, the largest exome study of congenital hypopituitarism published to date (137 Argentine cases) added evidence for PIBF1 and TBC1D32 and 13 candidate genes [18]. In the 2025–2026 window, CCDC149 was published, with two families and a murine model [62], and PNPLA6 with functional validation in a case of CPHD with visual loss [63].

1.2. Current nomenclature and classifications

CPHD is defined as GH deficiency associated with at least one other anterior pituitary deficiency (TSH, LH/FSH, PRL or ACTH); when all anterior pituitary axes are affected, the term panhypopituitarism is used [3, 4]. The French PNDS uses a different convention: it calls deficiency of at least two lineages multiple combined pituitary deficiency and reserves panhypopituitarism for combined anterior and posterior deficiency [19]. The English designation combined pituitary hormone deficiency (CPHD) and the alternative multiple pituitary hormone deficiency (MPHD) are equivalent; in Portuguese the term défice combinado de hormonas hipofisárias (DHHC) is used [2]. Since 2022, central diabetes insipidus has been called arginine vasopressin deficiency (AVP-D), and the nephrogenic form arginine vasopressin resistance, following a proposal by an international working group [64].

The OMIM classification numbers the forms by gene. Entry 613038, “pituitary hormone deficiency, combined or isolated, 1” (CPHD1, POU1F1, 3p11.2), has AD and AR inheritance, because dominance depends on the region of the protein affected and some variants have a dominant-negative effect, and it is the reference entry for genetic heterogeneity: CPHD2 (PROP1, 262600, AR, associated with hypogonadism), CPHD3 (LHX3, 221750, AR, with a rigid cervical spine and variable sensorineural deafness), CPHD4 (LHX4, 262700, AD), CPHD5 (HESX1, referred to septo-optic dysplasia, 182230), CPHD6 (OTX2, 613986, AD), CPHD7 (RNPC3, 618160, AR) and CPHD8 (ROBO1, 620303, AD) [5]. Three entries now use the designation “combined or isolated” (CPHD1, CPHD7 and CPHD8), and 618160 replaced the former designation “isolated growth hormone deficiency, type V” (IGHD5), because the same genes cause isolated GH deficiency (IGHD) or CPHD; OMIM cites that about 50% of IGHD progresses to CPHD [5, 10, 11]. The alternative titles record the history: 262600 retains “panhypopituitarism”, “ateliotic dwarfism with hypogonadism”, “pituitary dwarfism III” and “Hanhart dwarfism”; 221750, “deafness, sensorineural, with pituitary dwarfism”; 262700, “short stature, pituitary and cerebellar defects, and small sella turcica”; 312000 (X-linked panhypopituitarism, SOX3, Xq27.1), “pituitary dwarfism IV”; and 615849 (Culler-Jones syndrome, GLI2, AD), “Pallister-Hall syndrome 2” [6–8, 12, 13].

Orphanet uses a different hierarchical classification. The group ORPHA:467 (“non-acquired combined pituitary hormone deficiency”, with the synonyms congenital CPHD and congenital hypopituitarism) contains two categories, ORPHA:178025 (CPHD without extrapituitary malformations) and ORPHA:95495 (disorders associated with CPHD), and entities such as ORPHA:95494 (genetic forms; genes POU1F1, PROP1, HESX1, OTX2, LHX4, GLI2 and FOXA2), ORPHA:90695 (non-acquired panhypopituitarism; PROP1 and SOX3), ORPHA:231720 (LHX3), ORPHA:85442 (LHX4), ORPHA:226307 (hypothyroidism due to deficiency of pituitary transcription factors) and ORPHA:95496 (PSIS, classified as a morphological anomaly) [1–3, 14, 33, 34, 38]. The complete descendants of groups 467, 178025 and 95495 were not obtained, because the Orphadata classification endpoints returned an error during data collection.

The mappings between databases diverge and should be known. GeneGuidance associates X-linked panhypopituitarism (OMIM 312000) with ORPHA:67045 and OMIM 300123 with a congenital hypertrichosis; Orphadata associates 312000 with ORPHA:90695 and 300123 with ORPHA:67045 (“X-linked intellectual disability with isolated growth hormone deficiency”) [3, 49, 65]. Culler-Jones syndrome (OMIM 615849) corresponds in Orphadata to ORPHA:420584 (“postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome”), not to ORPHA:95494 [35, 50]. OMIM entry 613038 for POU1F1 also appears linked to ORPHA:231679 (IGHD type II), where Orphanet records POU1F1 with the term “gain of function”, reflecting the dominant variants with pure IGHD [37]. PSIS is treated by Orphanet as a morphological anomaly with associated genes, and a French exome series of 52 children proposed that it be seen as part of the spectrum of several genetic syndromes rather than as a specific entity [14, 66].

1.3. Definition of the entities in scope

This article covers congenital CPHD as a class: the classical transcription factor forms (PROP1, POU1F1, LHX3, LHX4, HESX1, OTX2), the X-linked forms (SOX3, EIF2S3), the Hedgehog pathway and axon guidance forms associated with PSIS (GLI2, CDON, ROBO1, GPR161), the forms with involvement of other organs (FOXA2, NFKB2, KCNQ1, RNPC3, PNPLA6) and the genes with recent evidence. Septo-optic dysplasia, with HESX1, SOX2, SOX3, OTX2, TCF7L1 and ARNT2 in the context of optic nerve hypoplasia, isolated congenital hypogonadotropic hypogonadism and Kallmann syndrome (ANOS1, FGFR1, PROKR2, FGF8, CHD7 and others), IGHD (GH1, GHRHR, GHSR, RNPC3 in the isolated form), GH insensitivity and the approach to neonatal and childhood hypoglycaemia appear here in the differential diagnosis. Other disorders with hypopituitarism as a component enter the differential: holoprosencephaly, CHARGE syndrome, Pallister-Hall and Greig syndromes, anterior segment dysgeneses with Axenfeld-Rieger, microphthalmia, anophthalmia and coloboma, congenital hyperinsulinism, primary congenital hypothyroidism, Börjeson-Forssman-Lehmann syndrome and monogenic obesity. Acquired deficiency (tumours, surgery, radiotherapy, trauma) and familial pituitary adenomas are outside the scope.

2. Molecular Genetics and Pathophysiology

2.1. Pituitary ontogeny and the transcription factor cascade

The anterior pituitary forms from Rathke's pouch, under signals from the ventral diencephalon, and differentiates five endocrine lineages: somatotrophs (GH), lactotrophs (PRL), thyrotrophs (TSH), gonadotrophs (LH and FSH) and corticotrophs (ACTH). The posterior pituitary, the stalk and the infundibulum derive from the diencephalon and contain the axons of the hypothalamic neurons that produce arginine vasopressin and oxytocin. The CPHD genes act at successive steps of this cascade, which explains the relationship between the gene, the axes affected and the extrapituitary findings.

HESX1 is a paired-like homeodomain repressor, expressed early in the prospective forebrain and later restricted to Rathke's pouch; it binds a palindromic site, heterodimerises with PROP1, antagonises transcriptional activation by PROP1 and represses target genes through the Groucho/TLE1 corepressors [48]. LHX3 and LHX4 are LIM homeodomain factors required for pouch formation and for the specification of all anterior pituitary lineages except the corticotroph lineage; LHX3 is also required for the development of motor neurons and interneurons, the basis of the cervical anomalies, and LHX4 transactivates the POU1F1 and GH promoters [21, 22]. OTX2 transactivates HESX1, POU1F1 and GNRH1 [23]. SOX2 and SOX3 maintain neural progenitors and are required for hypothalamic–pituitary development, including the infundibulum [49]. PROP1 precedes and is required for POU1F1 expression and directs the differentiation of somatotrophs, lactotrophs, thyrotrophs and gonadotrophs [4, 67]. POU1F1 specifies the somatotroph, lactotroph and thyrotroph lineages and directly activates the GH and PRL genes and, with GATA2, the TSH beta subunit gene [68]. TBX19 (TPIT) is required for terminal differentiation of corticotrophs and its loss causes isolated ACTH deficiency [69]. The Sonic hedgehog pathway (with GLI2 as effector and CDON as co-receptor), the ROBO/SLIT axon guidance pathway and primary cilia are involved in the formation of the midline, the stalk and the posterior pituitary, and their alterations are associated with an ectopic posterior pituitary (EPP) and PSIS [50, 51, 62, 70].

This organisation produces three clinical patterns. The terminal genes of the cascade (POU1F1) affect only GH, PRL and TSH, with a normal posterior pituitary and stalk; PROP1 adds the gonadotroph axis and, later, the corticotroph axis, also with a normal stalk and posterior pituitary; the early genes (HESX1, LHX4, SOX3, OTX2, GLI2, ROBO1) are associated with anterior pituitary hypoplasia, a thin or interrupted stalk, EPP and midline anomalies, with deficiencies of variable distribution [4, 24, 44]. In a British cohort of 1,765 patients, MRI was abnormal in all patients with variants in PROP1, GLI2, SOX3, HESX1, OTX2, LHX3 and LHX4, whereas the anatomy was normal in 24 of 121 patients with variants, mainly in GH1, GHRHR, POU1F1 and SOX2 [44].

2.2. Aetiological architecture of the class

More than 30 genes, syndromic and non-syndromic, are implicated, and 84–90% of cases remain without a molecular aetiology; the spectrum ranges from holoprosencephaly (HPE) to IGHD, with incomplete penetrance and variable expressivity [4, 71]. In a systematic review of 21 studies with at least 10 patients each, HESX1, LHX3, LHX4, PROP1 and POU1F1 explained 12.4% of CPHD (11.2% of sporadic and 63% of familial cases), with PROP1 as the most frequent gene (6.7% of sporadic and 48.5% of familial cases); in the multicentre Italian cohort of 144 patients from the same study, the frequency was 2.9% in sporadic and 12.5% in familial cases [41]. The yield rises with exome sequencing and with the inclusion of recent genes (19.1% in known genes and 16% in novel genes in an Argentine cohort of 137 cases, with variants of uncertain significance in 28.2%) [18], and the authors of the CCDC149 study estimate that only 10–15% of patients have an identified molecular basis [62]. Most cases are sporadic; the probability of a molecular diagnosis is higher in familial cases, in consanguinity and in phenotypes with a recognisable signature [24, 41].

2.3. Class table: genes, entities and distinguishing features

2.4. PROP1 (CPHD2)

PROP1 (5q35.3; NM_006261.5; three exons; protein of 226 amino acids, “homeobox protein prophet of Pit-1”) encodes a transcription factor with a paired-like homeodomain [4, 24]. Two conserved basic regions of the homeodomain ensure nuclear localisation, DNA binding and activation of target genes, and missense variants in these regions cause CPHD; the mechanism is loss of function, with reduced or absent DNA binding and transactivation [4, 85]. ACTH deficiency does not appear to result directly from the absence of PROP1 in corticotrophs; PROP1 overexpression in corticotrophinomas suggests a role in the differentiation or viability of these cells [4, 86]. Secretion of all hormones declines gradually with age, usually in the order GH, LH/FSH, TSH and ACTH [4].

Variants cluster in exon 2 and the homeodomain. A 2019 review classified the PROP1 variants published up to that date using the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria: 29 pathogenic, 2 likely pathogenic and 2 of uncertain significance (VUS), all on NM_006261.5 (NP_006252.4), among them two initiation codon variants (c.1A>G and c.2T>C, p.(Met1?)), splice variants (c.109+1G>A, c.109+1G>T, c.109+2T>G, c.342+1G>C, c.343-2A>T and c.343-11C>G), nonsense variants (p.Arg16Ter, p.Gln83Ter, p.Arg99Ter, p.Arg112Ter, p.Trp194Ter), homeodomain missense variants (p.Arg73Cys, p.Arg73His, p.Phe88Ser, p.Phe117Ile, p.Arg120Cys, p.Arg125Trp; VUS p.Arg71Cys, p.Arg71His and p.Arg121Thr) and frameshift deletions [24]. The two most frequent variants, c.301_302del and c.150del, are founder variants and not mutational hotspots: in a study of 237 patients from 21 countries, c.301_302del lay on a 0.2 Mb haplotype in most Europeans, with an estimated origin about 101 generations ago (confidence interval [CI] 90.1–116.4), and on a different haplotype in the Iberian Peninsula, at about 23.3 generations (20.1–29.1); both were transmitted to Latin American patients about 13.8 and 16.4 generations ago; c.150del lay on a haplotype of about 0.3 Mb at about 43.7 generations [87]. The Brazilian authors converted these estimates into a Baltic Sea haplotype of about 2,525 years, an Iberian haplotype of about 583 years and an origin of c.150del in the region of Belarus about 1,093 years ago [24]. In the recurrent sample, c.301_302del accounts for 55% of alleles in familial cases and 12% in simplex cases of CPHD [4].

OMIM brings together the families that founded the spectrum: 10 North American families in which 55% (11/20) of alleles were 301delAG, 8 of 14 Russian children with CPHD with PROP1 deletions (149delGA and 296delGA), a large Dominican family (8 patients aged 17 to 40 years with 296delGA), a Brazilian family with 10 patients homozygous for 301delAG and ACTH insufficiency in 5 of the 6 oldest, an Indian family with a 13 bp deletion and severe cortisol deficiency, and 9 of 23 French patients with variants in exon 2 and late ACTH deficiency in 4 [6]. OMIM keeps 301delAG (601538.0002) and 296delGA (601538.0005) as distinct historical alleles, whereas the current literature and ClinVar treat both designations as the same deletion c.301_302del [6, 24, 88]. There is no other germline phenotype associated with PROP1 [4]. Genotype–phenotype correlations are limited and the same variant gives different phenotypes within a family: in a Portuguese series, the presence and age at onset of hypocortisolism, PRL and imaging varied [89]. Spontaneous puberty followed by decline has been described with p.Arg120Cys, p.Phe88Ser and c.150del, whereas all carriers of c.301_302del in a Brazilian series had impaired gonadotroph function [90, 91]. The p.Trp194Ter variant in the homozygous state presented with hypogonadotropic hypogonadism and progressive GH and TSH deficiencies in adulthood, and a truncating variant in the transactivation domain caused familial central hypogonadism with GH and TSH deficiencies only in adulthood [71, 92]. There are no convincing examples of incomplete penetrance [71].

2.5. POU1F1 (CPHD1)

POU1F1 (PIT-1; 3p11.2; NM_000306.4) encodes a pituitary-specific POU homeodomain factor that binds the consensus element 5'-TAAAT-3' [68, 93]. Three mechanisms are established: simple loss of function (missense, nonsense, frameshift and splice variants, some substitutions with reduced protein stability), a classical dominant-negative effect (the protein binds DNA but does not transactivate) and a shift of alternative splicing towards the minor isoform POU1F1 beta, which is a transcriptional repressor; high-throughput splicing assays showed that missense and even synonymous variants can disrupt splicing [68]. Most variants are recessive, with hypoplasia and CPHD; of the approximately 30 variants reviewed in 2016, three were pathogenic dominant-negative variants, among them p.Arg271Trp and c.214+1G>T [71]. The p.Arg271Trp variant (NM_000306.4:c.811C>T) is a heterozygous hotspot, with complete penetrance in about half of cases and incomplete penetrance in two; it has conflicting classifications in ClinVar (VCV 13603) [71, 88].

Transactivation capacity is graded. In a functional study of 15 missense and nonsense mutants, P14L, P24L, F135C, K145X, F233S and E250X (published designations, on NP_000297.1: p.Pro14Leu, p.Pro24Leu, p.Phe135Cys, p.Lys145Ter, p.Phe233Ser and p.Glu250Ter) had reduced protein stability; transactivation of the TSH beta subunit promoter correlated moderately with that of the PRL promoter; and the mutants fell into three groups (wild-type-like, partial and substantially lost activity). In four patients with partial-activity variants, TSH deficiency became manifest only after recombinant GH (rhGH) was started; K216E (p.Lys216Glu) transactivated the TSHβ promoter like the wild-type protein and the PRL promoter poorly, and R271W (NM_000306.4:c.811C>T p.(Arg271Trp)) did the reverse [94]. A heterozygous variant, NP_000297.1:p.(Pro76Leu) (published designation), causes pure IGHD through a dominant-negative effect specific to the GH promoter, and homozygosity for p.(Gln4Ter) produced severe IGHD with PRL deficiency and without thyrotroph deficiency at 17 years, an exceptional course [95]. In a series of 13 patients from 6 families, the presentation varied between families and was constant within each, from multiple deficiencies with stalk interruption to IGHD, and a mother and daughter developed cortisol deficiency; there were heterozygous de novo variants and inheritance from an unaffected parent (incomplete penetrance) [5]. In the review of 114 patients, heterozygotes had a milder phenotype than homozygotes or compound heterozygotes (mean peak GH 1.1 versus 0.2 ng/mL; anterior pituitary hypoplasia in 63.6% versus 86.3%) [43].

2.6. LHX3 (CPHD3)

LHX3 (9q34.3; NM_178138.6) encodes a LIM homeodomain factor with at least six exons that binds the AATTAATTA motif, co-activates with LDB2 and synergises with POU1F1 on the PRL promoter; the isoforms have distinct functions in neuroendocrine and auditory development [21, 45, 93]. The founder variants were a missense variant in the LIM2 domain (Y116C) and an intragenic deletion producing a truncated protein lacking the homeodomain, both homozygous in consanguineous families [45]. In 2026 a homozygous homeodomain variant, c.575G>A p.(Arg192His), was described in a Turkish family with GH, TSH and PRL deficiency, intact ACTH, and normal pituitary MRI, neck and hearing, identified by exome sequencing at 10.5 years after a negative panel; the homozygous sister had the same endocrine phenotype [96]. In a screen of 366 patients from 342 families with pituitary insufficiency, LHX3 explained 7 patients (1.9%) from 4 families with CPHD and none of the 48 with IGHD, all with GH, PRL, TSH and LH/FSH deficiency; limited cervical rotation is not universal, re-evaluation of the 2000 patients revealed sensorineural deafness and ACTH deficiency was confirmed in one patient, which broadened the spectrum [7]. Inheritance is AR and Orphanet records 13 cases of the syndromic form [7, 33].

2.7. LHX4 (CPHD4)

LHX4 (1q25.2; NM_033343.4; six coding exons; protein 99% identical to the murine protein) encodes a LIM homeodomain factor with two non-redundant LIM domains, which has LHX3 as a protein partner [46, 59, 93]. The index family had a splice variant that activated two cryptic exonic sites, with proteins deleted in the homeodomain, and segregated with complete penetrance over three generations [59]. In a Franco-Italian cohort of 417 unrelated patients with IGHD or CPHD and EPP or a sellar anomaly, LHX4 sequencing found seven heterozygous variants, p.(Tyr131Ter), p.(Arg48ThrfsTer104), c.606+1G>T, p.(Ala65Val), p.(Thr163Pro), p.(Arg221Gln) and p.(Arg235Gln), all with variable expressivity and five with incomplete penetrance; the first five proteins tested did not transactivate the POU1F1 and GH promoters, and p.(Arg235Gln) was functionally normal and probably a rare polymorphism; the overall contribution was about 1.4% [46]. The p.(Arg235Gln) variant (c.704G>A) has conflicting classifications in ClinVar (VCV 801583), and the others have no ClinVar record under the protein notation [88]. OMIM adds a de novo missense variant (P366T) in a Japanese girl with severe respiratory distress and hypoglycaemia at birth, complete CPHD, a poorly developed sella and Chiari malformation, and three missense variants in 5 of 253 patients with CPHD and pituitary dysmorphism without cerebellar hypoplasia; the first compatible clinical description dates from 1969 (two sisters with a very small sella turcica) [8]. The recessive form has been described once: NM_033343:c.377C>T p.(Thr126Met) in the homozygous state in the LIM2 domain, in two siblings of Pakistani origin with severe panhypopituitarism and anterior pituitary aplasia who died in the first week of life despite promptly started hydrocortisone and thyroxine; the variant was absent in the homozygous state in more than 65,000 controls [47]. An inherited 1q25 microdeletion including LHX4 caused panhypopituitarism with potentially fatal heart failure [22].

2.8. HESX1 (CPHD5)

HESX1 (3p14.3; NM_003865.3) falls, in most cases, within the septo-optic dysplasia spectrum [93]. The founder variant of Dattani 1998, described as R53C in homeodomain numbering, corresponds to NM_003865.3:c.478C>T p.(Arg160Cys) [57, 93]. The mechanisms include abolition of DNA binding (p.Arg160Cys homozygous; p.Arg109Gln heterozygous), markedly reduced binding (p.Ser170Leu) and inability to recruit TLE1 with intact binding (p.Ile26Thr in the eh1 domain) [48]. Outside septo-optic dysplasia, a girl homozygous for p.Ile26Thr had evolving CPHD with a thin stalk, anterior pituitary hypoplasia and EPP, without midline anomalies or optic nerve hypoplasia, and a heterozygous patient with CPHD without features of septo-optic dysplasia presented with neonatal hypoglycaemia due to central adrenal insufficiency [48]. The 2016 review counted 8 pathogenic recessive variants and 14 heterozygous variants, of which only 4 were pathogenic loss-of-function variants; many heterozygous missense variants have incomplete penetrance or do not segregate [71]. In a cohort of 1,765 patients, 8 of 724 screened (about 1.1%) had HESX1 variants [44].

2.9. OTX2, SOX2 and SOX3

OTX2 (14q22.3; NM_021728.4) encodes a bicoid-type homeodomain factor that binds TCTAATCCC; haploinsufficiency is the mechanism (ClinGen haploinsufficiency score 3), through intragenic loss-of-function variants or whole-gene microdeletions, without a dominant-negative effect; frameshift alleles abolish transactivation of the HESX1, POU1F1 and GNRH1 promoters [23, 93]. The eye–brain–pituitary phenotype ranges from bilateral anophthalmia to isolated retinal dystrophy with normal globes, and pituitary involvement is independent of ocular severity: in a series of five patients with a variant, two had apparently normal pituitary function despite the ocular anomalies [23]. OTX2 explains 2–3% of anophthalmia and microphthalmia, about one third of carriers have pituitary deficiencies (19 of 55 in one review) and 42% of variants arise de novo; parental gonosomal mosaicism has been documented repeatedly [23, 71]. The OMIM entry for CPHD6 rests on two unrelated patients with a heterozygous OTX2 missense variant, found among 19 patients with hypopituitarism, described by the authors as dominant negative, with GH, ACTH, TSH and gonadotrophin deficiencies and EPP with an absent or very hypoplastic stalk; this description diverges from the GeneGuidance curation, which attributes the disorder to haploinsufficiency without a dominant-negative effect [9, 23]. The mechanism of an OTX2 variant with CPHD was clarified in hypothalamic–pituitary organoids derived from the patient's cells [97].

SOX2 causes anophthalmia or microphthalmia with hippocampal malformations, intellectual disability, oesophageal atresia and deafness and, on the pituitary axis, hypogonadotropic hypogonadism or CPHD with non-progressive pituitary masses; inheritance is AD with incomplete penetrance and maternal gonadal mosaicism has been described [71]. These forms overlap with septo-optic dysplasia and the microphthalmia–anophthalmia–coloboma spectrum.

SOX3 (Xq27.1; NM_005634.3) is a single-exon, dosage-sensitive gene: loss of function, alterations of the first polyalanine tract and duplications cause X-linked hypopituitarism [49, 93]. An expansion of 11 alanines was associated with intellectual disability with IGHD, an expansion of 7 alanines with panhypopituitarism without intellectual disability, and a 685.6 kb Xq27.1 duplication including SOX3 with a similar pituitary phenotype, showing that both underdosage and overdosage cause hypopituitarism; duplications of only 321 kb have been described [49]. In OMIM, entry 312000 describes two Finnish maternal half-brothers with neonatal hypoglycaemia and GH deficiency, anterior pituitary hypoplasia and a hypoplastic or absent lower infundibulum, and a consanguineous family from Qatar with four siblings with panhypopituitarism, both with SOX3 duplications and without intellectual disability; X-linked hypopituitarism with intellectual disability (300123) is allelic [12]. Affected boys have IGHD or CPHD, frequently anterior pituitary hypoplasia, EPP and an absent or hypoplastic infundibulum; female carriers are usually unaffected or mildly affected, and several boys inherited duplications from unaffected mothers [49]. Polyalanine expansion reduces transcriptional activity and nuclear localisation [49]. SOX3 duplications and regulatory rearrangements also cause 46,XX testicular or ovotesticular differences of sex development without SRY, and position effects are associated with congenital generalised hypertrichosis, neural tube defects, X-linked hypoparathyroidism and X-linked Charcot-Marie-Tooth neuropathy type 3 [49, 72]. ClinGen classifies the validity of the relationship with X-linked hypopituitarism as moderate (June 2026) [49]. A hemizygous p.Met304Ile variant was associated with IGHD with a hypoplastic anterior pituitary in a Brazilian series [78].

2.10. GLI2 and the Hedgehog pathway

GLI2 (2q14.2; MANE NM_001374353.1; transcript NM_005270 in the clinical sources) encodes the transcriptional effector of the Sonic hedgehog pathway, with a predominant full-length activator form and a repressor form obtained by proteolysis; the mechanism of the pituitary disorder is haploinsufficiency (ClinGen score 3) [50, 93]. In a series of 112 carriers, 43 had truncating variants, significantly more associated with pituitary anomalies with postaxial polydactyly, and only 1 of the 43 had overt HPE; the facies showed midface hypoplasia, cleft lip or palate and hypotelorism, sometimes subtle [50]. GLI2 missense variants of uncertain significance were not associated with the pituitary phenotype with polydactyly and should not be over-interpreted [50]. In the 2016 review, more than 20% of carriers had an unaffected carrier parent, one third had CPHD (83% without a syndrome) and 13% IGHD [71]. In HPE, GLI2 explained 3.1% of 257 patients, after SHH and ZIC2 and before SIX3 and FGF8 [98]. In a Brazilian screen of 41 patients with IGHD and 136 with CPHD, 24 had 18 heterozygous GLI2 variants (23 with CPHD and 1 with IGHD; 2 with AVP-D; EPP in 16 and posterior pituitary not visible in 4), none with signs of HPE, midline facial defects or polydactyly; the authors of a four-generation Brazilian family attributed the incomplete penetrance to complex inheritance with genetic and environmental factors [13]. A novel nonsense variant, c.3640C>T, caused Culler-Jones syndrome with PSIS and sensorineural deafness in a Chinese boy [99], and in the French GENHYPOPIT cohort the three GLI2 carriers had complete IGHD with EPP [95].

CDON (11q24.2) is a Hedgehog pathway co-receptor whose predisposition to HPE (HPE11) is AD with incomplete penetrance. A missense variant inherited from a mother with isolated short stature caused PSIS with CPHD and unilateral facial and abducens nerve palsy, and a nonsense variant inherited from the mother caused PSIS without HPE with GH, TSH and ACTH deficiencies and neonatal hypoglycaemia and cholestasis; the proposed model is multifactorial (Nodal and Hedgehog pathways and, in the mouse, synergy with fetal alcohol) [70]. GLI3, another effector of the pathway, causes Pallister-Hall syndrome through truncating variants that produce a functional repressor [16, 100].

2.11. Pituitary stalk interruption syndrome genes: ROBO1, GPR161 and the oligogenic model

PSIS is defined by the triad of a very thin or interrupted stalk, an ectopic or absent posterior pituitary and anterior pituitary hypoplasia or aplasia, or by isolated elements of the triad [14]. Before the exome era, HESX1, LHX4, OTX2, SOX3 and PROKR2 explained fewer than 5% of cases [51, 73]. ROBO1 (3p12.3; NM_002941.4), a receptor of the SLIT/ROBO axon guidance pathway, was associated with PSIS in five heterozygous cases: p.Ala977GlnfsTer40 in two siblings, p.Tyr1114Ter in a sporadic case and p.Cys240Ser in a child and the paternal aunt, with incomplete penetrance and ocular anomalies (hypermetropia with strabismus, ptosis) in four of five [51]. OMIM describes CPHD8 as an AD disorder with GH deficiency and variable TSH, ACTH and LH/FSH deficiencies, rare AVP-D and frequent PSIS, and adds a 4-year-old Chinese boy with hypoglycaemic seizures, CPHD and PSIS, whose mother had the same picture, with the missense variant P564S [11]. The recessive form, c.1342+1G>A in the homozygous state in a Japanese boy born to first cousins, associated CPHD with severe intellectual disability, sensorineural deafness, strabismus, dysmorphic features, a thin corpus callosum and hypoplasia of the pons and midbrain [60]. In the Argentine exome study of 137 cases, ROBO1 was the most frequently affected gene, with phenotypes beyond PSIS [18], and in a Brazilian and North American series of 78 patients with EPP it was found in four cases [101]. Besides the pituitary form, ROBO1 causes an AR neuro-oculo-renal syndrome (OMIM 620305) and congenital nystagmus [29].

GPR161 (an orphan G protein-coupled receptor, a ciliary regulator of the Hedgehog pathway) was proposed as a cause of PSIS on the basis of a homozygous missense variant in two affected siblings from a consanguineous Turkish family [73]. The second observation is a novel GPR161 variant in a Greek newborn with CPHD, compound heterozygous for ROBO1 and carrying a NOTCH3 variant, presented as an oligogenic hypothesis [74]. Orphanet lists GPR161 among the PSIS genes, and GeneGuidance considers the association not established and notes that the firm relationship of GPR161 is with predisposition to infantile SHH medulloblastoma [14, 102]; with one family and one oligogenic case, GPR161 is treated as a candidate gene with limited evidence. Exome sequencing of 52 French children with PSIS found rare variants in 37 families, in midline and pituitary genes (BMP4, CDON, GLI2, GLI3, HESX1, PROP1, PTCH1, SHH, TBX19, TGIF1 and others), hypogonadotropic hypogonadism genes (CHD7, FANCA, WDR11 and others), syndromic short stature genes, axon guidance genes (ROBO1, SLIT2) and corpus callosum agenesis genes; most had no functional validation [66]. In the EPP series, variants were found in 15 of 78 patients (19.2%), in 12 different genes, and the authors concluded that EPP is a multigenic disorder [101].

2.12. Other genes with CPHD

RNPC3 encodes a component of the minor spliceosome; biallelic variants cause severe IGHD with hypoprolactinaemia, variable TSH deficiency and anterior pituitary hypoplasia, with primary ovarian insufficiency in 8 of 9 women and normal male gonadal function; two men grew normally without GH despite severe biochemical deficiency [61]. OMIM records compound heterozygosity (for example, P474T with R502X, that is, p.Pro474Thr with p.Arg502Ter on NM_017619.4 (NP_060089.1), published designations, in three Romanian sisters), response to rhGH with a height gain of 4.0–5.9 SD after 4.5–6.5 years, normalisation of trabecular bone structure, red hair, obesity and myopathy in two siblings, and central hypothyroidism in a Caribbean sibship [10]. Additional phenotypes include congenital cataract, microcephalic primordial dwarfism, peripheral neuropathy and a severe form with cerebral and cerebellar atrophy, and there is also a form of isolated GH deficiency [28].

FOXA2 (20p11.21; NM_021784.5) causes, through variants that are usually de novo or 20p11.2 deletions, congenital hypopituitarism with anterior pituitary hypoplasia, an interrupted stalk or EPP, associated with neonatal-onset congenital hyperinsulinism, craniofacial dysmorphism, choroidal coloboma, malformations of endodermal organs (liver, lung, gut) and structural heart disease; pancreatic hypoplasia and late-onset diabetes have been described [40, 93]. ClinGen classifies the relationship with AD CPHD as moderate, with six variants in six probands, de novo when tested, and the 2024 international hyperinsulinism guideline lists FOXA2 as a diffuse AD syndromic form [40]. A truncating variant inherited from a father with only IGHD and a pituitary malformation was lethal in a fetus, showing variable intrafamilial expressivity [40]. An induced pluripotent stem cell (iPSC) line was created from a patient with FOXA2 p.(Ser229Ter) for mechanistic studies [103].

EIF2S3 (Xp22.11; NM_001415.4) causes MEHMO syndrome (intellectual disability, frequently refractory epilepsy, hypogonadism and hypogenitalism, microcephaly and obesity), with neonatal hypoglycaemia followed by early insulin-dependent diabetes and progressively declining hypopituitarism; the recurrent C-terminal frameshift p.Ile465SerfsTer4 (c.1394_1397del) gives the severe phenotype, and the hemizygous variant p.Pro432Ser (c.1294C>T) caused X-linked hypopituitarism (GH and TSH) with dysglycaemia, normal head circumference and mild learning difficulty [39, 88].

NFKB2 causes DAVID syndrome, a childhood-onset primary immunodeficiency more severe than typical common variable immunodeficiency: in an analysis of 50 patients (15 new and 35 published), 46 had early immunodeficiency, with mean onset at 5.9 years (median 4.0), autoimmunity in 80% and ACTH deficiency in 44%, potentially fatal during infection or surgery; most variants truncate the C-terminus of the p100 protein, with recurrent p.Arg853Ter (published designation, numbering compatible with NM_001322934.2) [30]. Gene editing in pituitary organoids confirmed that the endocrine phenotype is due to NFKB2, a central gene in pituitary development [97].

KCNQ1 encodes a potassium channel expressed in GHRH-producing hypothalamic neurons and in somatotrophs. In three families with maternally transmitted GH deficiency and gingival fibromatosis, the variants NP_000209.2 (NM_000218.3):p.(Arg116Leu) and p.(Pro369Leu), published designations, increased the channel current (with KCNE2) and reduced hormone secretion in AtT-20 cells [32]. A 6-year-old Japanese boy with p.(Pro369Leu), inherited from his mother, had short stature, gingival fibromatosis and dysmorphic features, with GH deficiency, central hypocortisolism, hypothalamic hypothyroidism and, at 12 years, hypogonadotropic hypogonadism, which extends the phenotype to CPHD [75]. The abstracts read do not explain the mechanism of maternal transmission. KCNQ1 is allelic with long QT syndrome type 1, Jervell and Lange-Nielsen syndrome, short QT type 2 and familial atrial fibrillation [31].

PNPLA6 causes, with AR inheritance, a continuum of cerebellar ataxia, upper motor neuron signs, chorioretinal dystrophy and hypogonadotropic hypogonadism, isolated or as part of anterior hypopituitarism, with the eponyms Boucher-Neuhäuser, Gordon Holmes, Oliver-McFarlane and Laurence-Moon [76]. In 2026, a 10-year-old girl compound heterozygous for p.Thr1115Pro (article numbering on NM_001166111.2:c.3343A>C; on the MANE transcript, NM_001166114.2:c.3313A>C p.(Thr1105Pro); NC_000019.10:g.7557200A>C) and an intronic variant creating a new splice acceptor (NM_001166111.2:c.3428-44G>A, with insertion of 14 amino acids, p.Pro1142_Ala1143ins14) had GH, TSH and gonadotrophin deficiency, visual loss and neurodevelopmental delay; both variants abolished neuropathy target esterase activity, and the gene is expressed in the SOX2+ stem cells of the pituitary primordium and, in the adult, in somatotrophs and corticotrophs [63].

CCDC149 was described in 2026: homozygous frameshift variants, p.Gly278Ter and p.Leu222Ter (published designations, numbering compatible with NM_001395273.1), in two unrelated families (three patients) with GH deficiency, hypogonadotropic hypogonadism and developmental delay or autism, severe scoliosis in one family and a small anterior pituitary in the other; the gene is expressed in the human embryonic hypothalamic–pituitary region, the null mouse has growth deficiency and reduced fertility, and the orthologue localises to the basal bodies of ciliated neurons, suggesting ciliary dysfunction; it is a strong candidate gene still without independent series [62]. PIBF1 and TBC1D32, ciliary genes, received evidence in the Argentine exome study, and a TBC1D32 variant was one of the five diagnoses in a Korean cohort [18, 77]. TGIF1 was associated with CPHD with AVP-D and signs of HPE (p.(Arg90Cys); published designations, numbering compatible with NM_003244.4) and with CPHD with pituitary aplasia and EPP (p.(Ser28Pro)), with AD inheritance and incomplete penetrance [78].

Other genes with hypopituitarism as part of a syndrome are BMP4 (syndromic microphthalmia 6 with pituitary anomalies and polydactyly, AD with incomplete penetrance) [79], TBX3 (ulnar-mammary syndrome, with pituitary hypoplasia and gonadotrophin and GH deficiencies in both sexes) [80], LEPR (severe early-onset obesity with hyperphagia and hypogonadotropic hypogonadism, listed among the causes of CPHD with central hypothyroidism) [81, 82] and SIX6 (the 14q22 deletion with SIX6 hemizygosity causes panhypopituitarism with early renal failure) [83, 84]. The genes of isolated hypogonadotropic hypogonadism (PROKR2, FGFR1, FGF8, CHD7 and others) can cause or overlap with CPHD [4, 25].

2.13. Normalised variants

The designations “296delGA” and “301_302delAG” refer to the same deletion in a GA repeat, which the 3' shifting rule of the Human Genome Variation Society (HGVS) nomenclature writes as c.301_302del; the equivalence is recorded in ClinVar and in the allele assignments of the original studies [87, 88, 93]. The LHX4 variants of Cohen 2017 and Gregory 2015, the LHX3 variant of Çetin 2026 and the TBX19 variant c.840del (published designation, NM_005149.3) were not validated in VariantValidator or found in ClinVar, and are kept in the articles' notation on NM_033343.4 and NM_178138.6 [46, 47, 96]. The POU1F1 p.Arg271Trp and LHX4 NM_033343.4 p.Arg235Gln variants have discordant evidence and are not presented as established pathogenic variants [88].

2.14. Endocrine pathophysiology, penetrance and modifiers

The common physiological consequence is loss of differentiated anterior pituitary cells or of their secretory capacity, with deficiencies that accumulate over life. In PROP1 deficiency, the pituitary may enlarge in childhood, fluctuate and involute; the masses operated on contained amorphous material without recognisable cells and the probable origin is the intermediate lobe, as in the Ames mouse [24, 104]. In the forms with PSIS, stalk interruption prevents transport of the hypothalamic hormones and is accompanied by anterior pituitary hypoplasia, and additional deficiencies appear after a median of about five years of follow-up [105]. GH influences the other axes: it inhibits 11-beta-hydroxysteroid dehydrogenase type 1, reduces conversion of cortisone to cortisol and can unmask secondary adrenal insufficiency, and it activates type 1 deiodinase and somatostatinergic tone, with a fall in free T4 (FT4) [106, 107].

Incomplete penetrance and variable expressivity characterise LHX4, HESX1, GLI2, OTX2, SOX2, SOX3, ROBO1, CDON, TGIF1 and the dominant POU1F1 variants, whereas PROP1, LHX3 and the recessive forms of POU1F1 behave as Mendelian disorders with complete penetrance [46, 50, 71]. The oligogenic and multifactorial model, with variants in several midline genes and a possible environmental contribution, explains part of PSIS and EPP [66, 70, 74, 101]. In the 2016 review of POU1F1, some carriers of the dominant p.Arg271Trp variant had cognitive or hearing impairment attributed to untreated maternal hypothyroidism during pregnancy, an environmental modifier of the phenotype [71].

3. Clinical Spectrum and Manifestations by System

3.1. Reference cohorts

The clinical descriptions rest on series from reference centres, with referred and treated patients. In a Korean tertiary centre, among 444 children with childhood-onset CPHD followed between 1994 and 2021, 43 had a congenital cause after acquired causes were excluded: the mean age at diagnosis was 3.2 years, 41.9% were diagnosed before 1 year, short stature was the most frequent presentation (37.2%, with a mean height z-score of −2.4), 23 (53.5%) had suggestive neonatal signs but only 15 of these were diagnosed in the first year, GH deficiency was present in 42 (97.7%), 33 (76.7%) had three or more deficiencies, 31 (72.1%) had extrapituitary phenotypes and 33 (80.5%) had abnormal MRI, which was associated with more deficiencies [77]. In a series from the Hospital das Clínicas of the University of São Paulo Medical School (HC-FMUSP), 14 patients with PROP1 variants (11 female) came to the first visit at a mean age of 16.3 years with a bone age delay of 6.0 years [24]. In Lithuania, 67 patients with CPHD were tested and 47 had biallelic PROP1 variants [42].

3.2. Neonatal period

The newborn with CPHD due to pituitary hypoplasia, PSIS or early genes may present with hypoglycaemia (due to GH, ACTH and cortisol deficiency), prolonged cholestatic jaundice, micropenis with or without cryptorchidism, hypotonia, poor weight gain, temperature instability, adrenal crisis and polyuria due to AVP-D [20, 27, 108]. The presence of midline lesions, such as cleft palate, is a clue [108]. In a Chinese series of 31 children with PSIS, the 10 with systemic onset (hypoglycaemia, cholestasis, micropenis or adrenal crisis) fell ill at 0.07 ± 0.04 years, against 2.68 ± 0.73 years in the 21 with predominant growth failure, but had a longer diagnostic delay (4.75 ± 1.26 versus 2.93 ± 1.02 years) and more ACTH (80.0% versus 33.3%) and LH/FSH (60.0% versus 9.5%) deficiencies at diagnosis [20]. In the most severe forms the course is fatal: the siblings homozygous for LHX4 p.(Thr126Met) were small for gestational age, with a small phallus, undescended testes and midface hypoplasia, and died in the first week [47]; in the original Pallister-Hall series, six newborns died in the neonatal period, with hypoadrenalism as the main cause of death [100].

PROP1 deficiency is the exception: unlike congenital CPHD of other aetiologies, newborns have no perinatal signs of hypopituitarism, birth weight and length are normal and neonatal hypoglycaemia and prolonged jaundice are rare [4, 24]. In the HC-FMUSP series, birth weight was 3,435 ± 390 g (+0.65 ± 0.92 standard deviations [SD]), 8 of 10 above the 50th centile, and 2 patients had prolonged jaundice [24]; in the Lithuanian series, birth length and weight were normal and 31% of boys had cryptorchidism [42]. Breech presentation is frequently associated with anterior pituitary insufficiency, according to the French PNDS, and in the EPP series it occurred in 5 of 15 patients with variants versus 1 of 63 without variants [19, 101]. Ophthalmological anomalies (mainly coloboma and optic nerve hypoplasia) are present in 10–20% of cases [19]. Neonatal presentation with hypoglycaemia due to central adrenal insufficiency has been described with heterozygous HESX1 variants [48], and the association of neonatal hyperinsulinaemic hypoglycaemia with hypopituitarism suggests FOXA2 [40].

3.3. Growth

Proportionate short stature, with growth deceleration and delayed bone age, is the most constant manifestation. In PROP1 deficiency, height is −1.5 ± 0.9 SD at 1.5 years and −3.6 ± 1.3 SD at 3 years, the age at which parents usually seek help, and bone age is −4.0 SD at 2.5 years; hands and feet are proportionately small [4]. In Lithuania, median height SD in years 1 to 5 was −1.56, −2.34, −3.43, −3.52 and −3.70, and parental target height predicted severity (r² = 0.30) [42]. In POU1F1 deficiency, growth failure is severe and often present from birth, with a prominent forehead, marked midface hypoplasia, a depressed nasal bridge, deep-set eyes and a short nose [68]. In PROP1 deficiency, an “immature” face, a depressed nasal bridge and a relative reduction of vertical facial dimensions are described, with intelligence usually normal and obesity rare in childhood and more common in adulthood [4].

3.4. Thyrotroph axis

Central hypothyroidism is characterised by low FT4 with low, normal or slightly elevated TSH [27]. In POU1F1 deficiency it is early and often moderate to severe: in the Mumbai cohort, TSH deficiency was diagnosed earlier (median 6 months) than GH deficiency (median 3 years), and in the review of 114 patients the thyrotroph axis was preserved in only 12.5% [43]. In PROP1 deficiency, hypothyroidism is rarely the presenting feature; it usually appears at the end of infancy or in childhood, with or after GH deficiency, is mild and does not cause intellectual disability; it may exist with an apparently normal axis (normal basal TSH, slightly reduced FT4 and an insufficient response to thyrotrophin-releasing hormone, TRH), and the mean age at diagnosis was 6.8 years in one series [4, 24]. In Lithuania, GH and TSH deficiencies were diagnosed in all 44 patients assessed, at median ages of 5.5 and 5.6 years [42].

3.5. Gonadotroph axis

In the male newborn, gonadotrophin deficiency manifests as micropenis (stretched length below 2.5 cm at term) and cryptorchidism [4]. Later, puberty is absent or delayed and incomplete: in boys, small penis and testes and puberty after 14 years or arrest of development; in girls, absent thelarche or late menarche; and infertility in both sexes [4]. In PROP1 deficiency, gonadotrophin deficiency affects practically all patients, with a median age at diagnosis of 15.0 years in Lithuania (22 of 44), and some girls have spontaneous menarche before needing replacement [4, 42]. In POU1F1 deficiency gonadal function is intact, and in the Mumbai cohort two sisters had central precocious puberty at 7 years, although pubic hair was deficient in all post-pubertal patients [43]. Gonadotrophin deficiency also predominates in CHD7 (50–70%), TBX3, PNPLA6, CCDC149, LEPR and SOX2, and in RNPC3 the failure is primary ovarian and not pituitary [15, 61, 62, 76, 80].

3.6. Corticotroph axis

ACTH deficiency is the most dangerous, because adrenal crisis can be fatal. In the forms with PSIS and early genes it is frequently present from the neonatal period [20, 48]. In PROP1 deficiency it appears mainly in adolescence or adulthood, with onset between 11 and 63 years, manifests as persistent weakness, abdominal pain, anorexia and weight loss, and neonatal presentation and signs of acute deficiency have not been described; adrenal function declines gradually, even after more than four decades [4]. In a literature review, the mean age at diagnosis of ACTH deficiency in PROP1 deficiency was 25.3 years (7.4–67), and in the HC-FMUSP series seven patients progressed to ACTH deficiency at a mean age of 28 years (11.9–52.1) [24]. In Lithuania, 19 of 44 patients had ACTH deficiency at a median age of 13.1 years [42]. In LHX3 deficiency the corticotroph axis is typically spared, in POU1F1 deficiency it is preserved, and in DAVID syndrome ACTH deficiency affects 44% of patients and may appear many years after the immunodeficiency [21, 30, 68]. The untreated acutely ill patient presents with hyponatraemia, hypoglycaemia and, sometimes, hyperkalaemia; renin and aldosterone are normal in the secondary form [4].

3.7. Prolactin and lactation

PRL deficiency has few consequences beyond inability to breastfeed in the adult woman [4]. In POU1F1 deficiency it is almost always present (preserved in 4.4% of the 114 patients), and low or undetectable PRL is a diagnostic clue [43, 68]. In PROP1 deficiency it affects 30–80% of patients, between 3 months and 14 years [4]. In RNPC3 deficiency hypoprolactinaemia accompanies severe IGHD [61]. In midline defects, PRL is often elevated in the neonatal period [17].

3.8. Posterior pituitary

AVP-D is rare in the terminal transcription factor forms and more frequent when the posterior pituitary is not visible. In a Polish series of 50 children with PSIS, all AVP-D occurred in patients without a visible posterior pituitary [109], and in classical HPE AVP-D affects about 70% of surviving children [50]. It has been described once in ROBO1-related PSIS and has been associated with TGIF1 [29, 78]. Cortisol deficiency reduces free water excretion and can mask AVP-D, which is revealed after hydrocortisone is started [17].

3.9. Phenotypes by gene

Source: [4].

In LHX3 deficiency, complete GH, TSH, LH, FSH and PRL deficiency is accompanied by a rigid cervical spine with limited head rotation, cervical vertebral malformations, scoliosis, mild developmental delay and moderate sensorineural deafness; MRI shows severe hypoplasia in some patients and a secondarily enlarged anterior pituitary in others, so a normal or large pituitary does not exclude the diagnosis [21, 45]. Some patients have additional respiratory and skeletal abnormalities [71], and the homeodomain variant p.(Arg192His) showed that endocrine deficiency can occur without structural, auditory or motor anomalies [96].

In LHX4 deficiency, short stature with complete or partial deficiencies is accompanied by hindbrain and cerebellar defects (pointed cerebellar tonsils, Chiari malformation), a small sella turcica, a small anterior pituitary and, in some patients, EPP; expressivity is variable within the same family [22, 34]. In OTX2 deficiency, pituitary function ranges from IGHD with an abnormal pituitary to complete CPHD with neonatal hypoglycaemia, and it is associated with psychomotor developmental delay, joint laxity, hypotonia and seizures in some patients [23]. In GLI2 deficiency, Culler-Jones syndrome combines EPP or a non-visible posterior pituitary, IGHD or CPHD, postaxial polydactyly and midline facial defects, and a child identified by polydactyly or a subtle facial difference may have unrecognised hypopituitarism [50]. In SOX3 disorders, boys have IGHD or CPHD with or without intellectual disability and, sometimes, corpus callosum anomalies; a boy with an Xq26.3-q27.1 duplication went from −5.87 SD to −1.78 SD in two years with levothyroxine and then rhGH [49]. In MEHMO syndrome and PNPLA6 disorders, the neurological and ocular manifestations dominate the picture [39, 76]. In DAVID syndrome, recurrent sinopulmonary infections due to hypogammaglobulinaemia precede symptomatic ACTH deficiency, sometimes by many years [30, 36].

3.10. Syndromes with hypopituitarism

In Pallister-Hall syndrome (GLI3), the hypothalamic hamartoma replaces the hypothalamus from the optic chiasm to the interpeduncular fossa and is associated with pituitary aplasia or dysplasia with panhypopituitarism, imperforate anus, postaxial or mesoaxial polydactyly, bifid epiglottis, heart disease and renal anomalies; the endocrine manifestations range from isolated IGHD or isolated precocious puberty to potentially fatal panhypopituitarism, and cortisol deficiency occurs in the non-familial form and is rare in the familial form [16, 100]. In CHARGE syndrome (CHD7), hypogonadotropic hypogonadism affects 50–70% of patients, growth failure 70% (due to GH deficiency in about 10%) and hypothyroidism 15–20%, with a J-shaped sella and an ectopic pituitary on imaging [15, 110]. Börjeson-Forssman-Lehmann syndrome (PHF6) includes apparently hypogonadotropic hypogonadism and, occasionally, panhypopituitarism [111]. In Axenfeld-Rieger syndrome (PITX2), an abnormal sella turcica and GH deficiency are part of the anomalies, and PITX2 contributes to terminal differentiation of somatotrophs and lactotrophs [112, 113]. In HPE, the midline structures, including the hypothalamus and pituitary, are frequently affected and hypothalamic–pituitary dysfunction is common [98].

3.11. Untreated natural history and treated disease

The untreated natural history is known only from late cases. Five Serbian siblings homozygous for PROP1 c.301_302del, never treated, were assessed between 36 and 51 years of age: short stature of −3.7 to −4.7 SD, infantile sexual characteristics, moderate abdominal obesity, low bone mineral density in three, complete hypopituitarism in three and GH, TSH, FSH and LH deficiency in the other two; once replacement was started, including rhGH, all needed hydrocortisone after a few months, and after two years bone mineral density and body composition had improved in all [114]. Untreated affected siblings usually have extreme short stature [4]: in a large consanguineous Tunisian family, 13 of 28 relatives examined had hypopituitarism, and in the 14 never-treated patients height was −5.7 ± 1.7 SD and puberty began spontaneously in only two women [6]. In treated disease, GH started early allows familial height to be reached [4]: in Lithuania, with GH at 0.027 mg/kg/day, median growth velocities were 12.2, 9.1 and 6.9 cm/year in the first three years, and the final height of 17 patients was −0.98 ± 1.77 SD, 1.04 ± 1.41 SD below target height [42]. In the HC-FMUSP series, height at the first visit ranged from −2.5 to −9.4 SD, reflecting late diagnosis [24]. Among the 17 Korean patients re-evaluated in adulthood, all had persistent GH deficiency and 10 (58.9%) had metabolic abnormalities [77].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In the newborn, suspicion arises with persistent or recurrent hypoglycaemia, prolonged jaundice or cholestasis, micropenis with or without cryptorchidism, hypotonia, poor weight gain, haemodynamic instability or polyuria, especially when there are midline anomalies (cleft palate, hypotelorism), ocular anomalies, polydactyly or a family history [23, 27, 50, 108]. Newborns with signs of congenital hypopituitarism should undergo endocrine testing, even if newborn screening was normal [27]. The absence of neonatal signs does not exclude the diagnosis, because PROP1 deficiency typically presents without them [4]. The French PNDS adds that neonatal bilateral cryptorchidism requires urgent specialist assessment, that the signs of neonatal hypothyroidism are often scant or absent and that birth length is usually normal [19].

In infancy and childhood, the main sign is growth deceleration. The Growth Hormone Research Society (GRS) recommends assessing children with height below −2 SD, height clearly outside the family context or deceleration of at least 0.3 SD per year not explained by catch-down, and does not require a height threshold for the diagnosis in infants with hypoglycaemia, midline defects or recent-onset deficiency [115]. The European Thyroid Association (ETA) recommends screening for central hypothyroidism in all children with a family history, poor growth, developmental delay, GH deficiency, delayed or precocious puberty or other hypothalamic–pituitary defects [25]. The French PNDS uses as warning signs height below −2 SD or −1.5 SD from parental target height, a change of growth channel greater than 0.5 SD in one year, absence of breast development after 13 years or of a 4 mL testicular volume after 14 years, and polyuria above 100–110 mL/kg/day up to 2 years and 40–50 mL/kg/day thereafter, without glycosuria; MRI may be normal without excluding the diagnosis [19]. Low PRL, early central hypothyroidism and the absence of other deficiencies suggest POU1F1; cervical rigidity with deafness, LHX3; polydactyly, GLI2; ocular anomalies, OTX2, SOX2 or HESX1; immunodeficiency with recurrent infections, NFKB2; and gingival fibromatosis, KCNQ1 [21, 23, 30, 32, 50, 68].

In adolescence and adulthood, absent or incomplete puberty in a person with treated or untreated short stature, primary amenorrhoea, infertility or inability to breastfeed suggest CPHD, and weakness, anorexia, abdominal pain and weight loss suggest late-onset ACTH deficiency [4]. In an adult with known CPHD of genetic cause, every new non-specific symptom should prompt reassessment of the corticotroph axis, especially after GH has been started [4, 114].

4.2. Warning and emergency signs

4.3. Newborn screening

There is no newborn screening for CPHD. Programmes based on TSH alone do not detect central congenital hypothyroidism, which has a maximum reported incidence of about 1/16,000; more than half of these newborns have moderate to severe hypothyroidism (initial FT4 of 5–10 pmol/L or less), often with other pituitary deficiencies, and the diagnosis is frequently late [27]. The Endo-ERN initiative, endorsed by the European Society for Paediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE), suggests screening with T4 (total or free) in addition to TSH where resources allow, and clinical suspicion with a normal TSH on screening should prompt evaluation for central hypothyroidism [27]. Dutch screening, because it uses T4, detects central hypothyroidism and showed that, among children with isolated central congenital hypothyroidism who were tested, 53% had IGSF1 variants and 16% TBL1X variants [116]. On the newborn screening card, a GH threshold of 7 µg/L measured by ultrasensitive polyclonal enzyme immunoassay had 100% sensitivity and 98% specificity in a study cited in the Bosch i Ara review, but it does not constitute an implemented screening programme [17].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria and principles

CPHD is diagnosed by documenting deficiency of GH and of at least one other anterior pituitary axis [4]. There are no formal consensus criteria for the class; the criteria by axis in the following table come from the PROP1 GeneReviews and from the guidelines for each axis. Diagnosis of the genetic form requires pathogenic or likely pathogenic variants in the corresponding gene, with the appropriate inheritance: in PROP1 deficiency, biallelic variants; biallelic VUS, or one pathogenic variant with one VUS, neither establish nor exclude the diagnosis [4]. The French national diagnosis and care protocols (PNDS) for children and adults, prepared by the HYPO and CRMERCD reference centres, recommend testing all axes, obtaining MRI with thin sections centred on the hypothalamic–pituitary region and performing genetic testing by next-generation sequencing (NGS) of the pituitary development genes, array comparative genomic hybridisation (array-CGH) or genomic analysis, with early MRI in the newborn and in severe hormone deficiency [117, 118]. The diagnosis of GH deficiency remains clinical, through synthesis of auxology, anatomy and laboratory findings, and should not rest on laboratory tests alone [115].

GnRH: gonadotrophin-releasing hormone; hCG: human chorionic gonadotrophin; IGF-I: insulin-like growth factor 1; IGFBP-3: IGF binding protein 3.

5.2. Assessment in the newborn and infant

GH stimulation tests are dangerous and contraindicated in the neonatal period and below 1 year of age [17]. In the newborn, GH is physiologically elevated in the first week; a random GH of 5 µg/L or less in the first 7 days, with other deficiencies or with the imaging triad (EPP, anterior pituitary hypoplasia and an abnormal stalk), suffices to diagnose GH deficiency [17]. The GRS considers that a random GH below 7 µg/L in the first week of life supports the diagnosis in a newborn with high pre-test probability, and that a stimulation test is unnecessary in infants with hypoglycaemia, hyperbilirubinaemia, poor growth, midline defects, micropenis, low IGF-I and IGFBP-3, multiple deficiencies or abnormal MRI [115]; a random GH above 7 µg/L in the first week reliably excludes deficiency, and spontaneous hypoglycaemia (critical sample with glucose below 40 mg/dL) with GH below 10 µg/L probably establishes the diagnosis [119]. The threshold “<7 ng/dL” written in the PROP1 GeneReviews corresponds to 7 µg/L (ng/mL), the unit used by the guidelines [4, 115]. IGF-I is not useful for neonatal screening, because it remains low until 15–18 months [17]. The 2016 Pediatric Endocrine Society (PES) guideline suggests diagnosing the GH deficiency of congenital hypopituitarism without formal testing in a newborn with hypoglycaemia whose GH does not exceed 5 µg/L and who has at least one other pituitary deficiency and/or the imaging triad (conditional recommendation, low-quality evidence) [120]. The basis is limited: in a retrospective study with an assay validated on dried blood spots on filter paper, the median GH of 314 newborns under 5 days old was 16.4 µg/L (95% confidence interval 7–39.4 µg/L), whereas 9 newborns with multiple deficiencies, sampled between 5 and 28 days of life, had 5.5 µg/L or less in the same assay; and, among 44 patients with congenital GH deficiency, no newborn with IGHD had hypoglycaemia, against 60–70% of those with panhypopituitarism, with or without imaging abnormalities [120]. The neonatal cholestasis with hypoglycaemia of panhypopituitarism improves with hormone replacement, including GH [120]. After the first week there are no GH thresholds that separate the normal from the deficient newborn, and the PES considers that a low GH during spontaneous hypoglycaemia is not, on its own, sufficient for the diagnosis, owing to low specificity outside the neonatal period; this position is more restrictive than the Yuen 2023 reading above, because the PES also requires another deficiency or the characteristic imaging [119, 120].

On the corticotroph axis, newborns do not have an established circadian rhythm, so morning cortisol is not useful; low cortisol during hypoglycaemia has low specificity and should not be the only test, and many need a tetracosactide test, whose protocol is controversial; a stimulated cortisol of 18 µg/dL (497 nmol/L) or more indicates a normal axis [17]. A random cortisol suffices as a first assessment in the newborn, and above 1 year the 8 a.m. cortisol is used [121]. Minipuberty (15 days to 6 months in boys, with a testosterone peak at 4–10 weeks; 15 days to 2 years in girls) is the window for documenting gonadotrophin deficiency in the infant [17]. When AVP-D is suspected, neonatal polyuria is defined as urine output above 5 mL/kg/h, a urine osmolality above 600 mOsm/kg makes AVP-D unlikely, and the water deprivation test and the vasopressin test are not performed in the newborn [17].

5.3. Somatotroph axis after the neonatal period

Stimulation tests are performed fasting and after the other deficiencies (hypothyroidism and hypogonadism) have been corrected; there are no data showing superiority of any stimulus; insulin-induced hypoglycaemia, glucagon, arginine, clonidine and L-dopa are used; GH-releasing hormone (GHRH) is not appropriate in children because it does not detect hypothalamic or stalk deficiency [115]. Assays with monoclonal antibodies and recent standards give values about 40% lower than the older ones, and most experts suggested revising the paediatric threshold to about 7 µg/L, depending on the assay [115, 119]. Severe deficiency is frequently defined by a peak below 3 µg/L with high pre-test probability, and a GRS Delphi survey reached consensus that a peak below 5 µg/L is consistent with severe deficiency in children and that subnormal IGF-I is diagnostic in panhypopituitarism [115, 122]. Sex steroids increase stimulated GH before Tanner stage III; the GRS consensus limits this priming to adolescents with suspected constitutional delay of growth and puberty, notes that most GH deficiencies diagnosed in the peripubertal period turn out to be constitutional delay and recommends reconsidering the diagnosis after the end of growth when MRI is normal; the Pediatric Endocrine Society (PES) supported priming in prepubertal children (boys over 11 years and girls over 10 years) [115, 119]. Identification of a genetic cause can guide treatment, provide prognostic information, facilitate surveillance of associated conditions, end the diagnostic odyssey and allow counselling and identification of other relatives [115]. Oral macimorelin is not a paediatric test: in a randomised crossover trial in 102 children aged 3 to 17 years, diagnostic accuracy was not demonstrated, and the indication remains restricted to adults [123].

The PES guideline (2016) dispenses with stimulation testing when three conditions coexist: auxological criteria, a hypothalamic–pituitary defect (major congenital malformation, such as EPP with pituitary hypoplasia and an abnormal stalk, tumour or irradiation) and deficiency of at least one other pituitary hormone (conditional, low-quality evidence); with high suspicion without these conditions, the conventional route is followed [120]. It recommends not using the test results as the sole diagnostic criterion (strong, high-quality evidence) and requires an inadequate response to two different tests, which may be performed sequentially on the same day [120]. In classical deficiency, the values are far from normal: in a series of 63 treated patients, the 15 with imaging abnormalities had a peak below 5 µg/L; in the GeNeSIS registry, the median peak was 2.7 µg/L in 1,071 patients with deficiency and any imaging abnormality; in KIGS, the mean was 3.1 µg/L with imaging abnormalities (excluding hypoplasia), 4.9 µg/L with pituitary hypoplasia and 6.6 µg/L in idiopathic deficiency [120]. The 10 µg/L threshold has no controlled reference standard: it lies just below the mean response of children with normal growth, whose 5th centile is below 5 µg/L in most tests; in the North American NCGS registry (236 prepubertal children), the gain in height score in the first year did not differ between peaks of 5–10 µg/L and above 10 µg/L, gains greater than 1.5 SD occurred only with peaks below 5 µg/L and the specificity of the 10 µg/L threshold was estimated at 25% [120]. Reproducibility is imperfect (correlation between the peaks of two tests in the same patient of 0.35–0.6 in a French registry of 3,233 cases; 0.72 for the ITT in duplicate), the response decreases with BMI without validated adjusted paediatric cutoffs, and hypothyroidism and hypercortisolism should be excluded before testing because they falsely lower GH [120]. The PES recommends that laboratories use assays harmonised with the somatropin IRP IS 98/574 standard (22 kDa recombinant isoform) (strong): differences between assays misclassified up to 29% of 132 patients in a study with three reference assays and 27% in a German harmonisation effort before correction, and in Japan harmonisation lowered the threshold from 10 to 6 µg/L [120]. For priming, the PES proposes, in boys and girls, 2 mg of oestradiol (β-oestradiol, not ethinylestradiol) orally (1 mg below 20 kg) on the two nights before the test or, in boys, 50–100 mg of depot testosterone IM one week before; the recommendation applies to patients without prior GH and with a predicted adult height within −2 SD, and the PES advises against (strong) measuring spontaneous GH secretion for diagnosis [120].

In the adult, the cutoffs accepted in the USA and Europe are 3.0–5.0 µg/L in the insulin tolerance test (ITT) and, for glucagon, 3.0 µg/L with a body mass index (BMI) below 25 kg/m² and 1.0 µg/L with a BMI of 25–30 kg/m² and low pre-test probability or with a BMI of 30 kg/m² or more; macimorelin has a cutoff of 2.8 µg/L [119]. The Brazilian guideline uses the ITT with a peak below 3 µg/L (below 5 µg/L in transition) and glucagon with a peak below 3 µg/L (below 1.0 µg/L in overweight), and considers that, with multiple deficiencies and a documented structural lesion, a low IGF-I suffices [106]. With three or more pituitary deficiencies and a low IGF-I, the diagnosis of adult GH deficiency is as specific as any test [119, 124].

5.4. Thyrotroph axis

Central hypothyroidism is diagnosed by low FT4 with low, normal or slightly elevated TSH, after exclusion of non-thyroidal illness, prematurity and thyroid hormone resistance [27]. Total T4 can replace FT4 in childhood-onset central hypothyroidism; TRH and T3 have no diagnostic usefulness in the adult, and a fall in FT4 greater than 20% during follow-up raises the alert for central hypothyroidism even within the reference range [106]. The ETA recommends considering the diagnosis with FT4 in the lower quartile or with a fall greater than 20% and low or normal TSH in the same assay, and assessing for the appearance of central hypothyroidism after starting rhGH or oestrogen [25]. Biotin interferes with immunoassays and should be stopped at least two days beforehand [125]. In POU1F1 and PROP1 deficiency, the TRH test shows a TSH peak with an abnormal increment (below 5 mU/L) and a low PRL peak, a pattern of pituitary rather than hypothalamic defect [24].

5.5. Corticotroph axis

In the adult and the older child, an 8–9 a.m. cortisol below 3 µg/dL (100 nmol/L) is strongly predictive of secondary adrenal insufficiency, a value above 15 µg/dL excludes it, and between 3 and 15 µg/dL testing is needed; the ITT is the reference (peak below 18 µg/dL, or about 12 µg/dL with immunoassays calibrated by mass spectrometry), contraindicated in epilepsy, arrhythmias and cerebrovascular disease; glucagon has lower sensitivity and specificity; the 250 µg tetracosactide test confirms deficiency with a peak below 18 µg/dL, may be falsely normal in partial forms, and tetracosactide has limited availability in Brazil [106]. Cortisol should be sampled at least 24 h after the last dose of hydrocortisone; oral oestrogen increases serum cortisol by 20–50% through an increase in binding globulin; plasma ACTH has no value in the diagnosis of the secondary form; and testing should never delay hydrocortisone when crisis is suspected [106]. In the Brazilian PROP1 series, partial ACTH deficiency was defined by basal cortisol above 5.0 µg/dL with a peak below 18.1 µg/dL [24].

5.6. Gonadotroph and lactotroph axes

In adolescence and in the adult, hypogonadotropic hypogonadism is defined by low oestradiol or low total testosterone (sampled before 10 a.m., fasting, in two determinations in the same assay if borderline) with low or inappropriately normal LH and FSH, without the need for stimulation tests [106]. Before the age of puberty, the diagnosis is possible only during minipuberty or through neonatal signs [17, 126]. Basal PRL is sampled at diagnosis; in the neonatal period, the breast should not be palpated before sampling [4, 17].

5.7. Hypothalamic–pituitary magnetic resonance imaging

Brain and pituitary MRI is indicated in all suspected or confirmed cases, with 2–3 mm high-resolution T1 and T2 sections in the coronal and sagittal planes, and should describe the dimensions of the anterior pituitary, the location and size of the posterior pituitary, the stalk, the chiasm, the septum pellucidum and the corpus callosum; the posterior pituitary bright spot is absent in 10% of healthy people [17]. MRI is not a diagnostic test for GH deficiency, but it predicts other deficiencies, the usefulness of genetic testing and the persistence of the deficiency; the most suggestive findings are an absent anterior pituitary, EPP and hypoplasia of the stalk or pituitary, and an isolated small pituitary is not sufficient [115]. In a cohort from Great Ormond Street Hospital (GOSH) in London diagnosed between 1994 and 2015, among the 53 patients with multiple pituitary deficiency without septo-optic dysplasia or optic nerve hypoplasia, anterior pituitary anomalies were present in 98.0%, a small anterior pituitary in 96.0%, EPP in 80.0%, stalk anomalies in 46.9% and the PSIS triad in 46.9% [127]. In PSIS, progression to CPHD was 87.5% with stalk agenesis and 33.3% with hypoplasia [109].

Imaging distinguishes the major genetic groups. In PROP1 and POU1F1 deficiency, the stalk and posterior pituitary are normal (eutopic posterior pituitary) and the anterior pituitary is hypoplastic, normal or enlarged [24, 68]. In PROP1 deficiency, the pituitary may be enlarged in childhood, enlarge and shrink before reducing in adolescence or adulthood and involute completely, and it may mimic a pseudotumour, non-functioning adenoma, craniopharyngioma or Rathke's cleft cyst [4]; in a girl aged 8.8 years, a diffusely enlarged pituitary with T1 hyperintensity decreased from 8 mm to 2 mm at 15 years, and in a British series a mass enlarged and shrank over 20 months before involution [24, 104]. In Lithuania, pituitary height in PROP1 deficiency ranged from 16.6 mm (+20.2 SD) to 1.4 mm (−15.5 SD) and decreased with age [42]. In a longitudinal follow-up of 15 patients with PROP1 deficiency, the pituitary was small in 7 (mean age 25.2 years), normal in 3 (10.2 years) and enlarged in 5 (6.5 years), and the enlargement corresponded to a non-enhancing mass interposed between the anterior lobe and the posterior pituitary, with the stalk displaced forwards [6]. In the HC-FMUSP series, 11 of 14 patients had hypoplasia, one progressed from hyperplasia to normal or hypoplasia, two had a normal pituitary and two had hypointense nodules of 3.0 and 3.2 mm interpreted as microadenomas [24]. In the early genes and in PSIS, EPP, a thin or interrupted stalk and midline anomalies are the rule; in LHX4 deficiency, the sella turcica is small and the cerebellar tonsils pointed; in LHX3 deficiency, the pituitary may be enlarged; in Pallister-Hall syndrome, the hypothalamic hamartoma is a non-enhancing mass in the floor of the third ventricle, isointense to grey matter [16, 21, 22]. Ophthalmological assessment is recommended in congenital hypopituitarism [17].

5.8. Genetic testing

The ETA recommends genetic analysis in cases of central hypothyroidism that are congenital, of childhood onset or unexplained, and exome, genome or array-CGH when the panel is negative [25]; the Endo-ERN initiative recommends genetic testing in central congenital hypothyroidism [27]. The PROP1 GeneReviews proposes two approaches: when the phenotype is distinctive (CPHD with a eutopic posterior pituitary, gonadotrophin deficiency, absence of neonatal signs), PROP1 sequencing followed by targeted testing for deletions and duplications if zero or one variant is found, targeted analysis of the founder variants in people of Hutterite, Indian, Eastern European or Iberian ancestry, or a multigene CPHD panel; when the phenotype cannot be distinguished from other causes, exome (most used) or genome [4]. The Brazilian authors consider Sanger sequencing of PROP1 an appropriate first step in CPHD with a eutopic posterior pituitary in high-prevalence regions (Brazil, Eastern Europe), followed by a panel or exome [24, 91]. The full text of the French PNDS recommends, outside specific syndromic forms and already documented familial forms, an NGS panel of the most prevalent genes in the index case, also capable of detecting copy number changes, supplemented or preceded by array-CGH in syndromic forms (higher probability of a contiguous gene syndrome), a clinical genetics consultation first in syndromic forms and, when all analyses are negative, trio genome sequencing as second line, available in France since 2020 [19]. The same document stresses that the genetic result guides surveillance: a patient with a POU1F1 variant will have somatotroph and thyrotroph deficiencies from childhood without other deficiencies, whereas a patient with PROP1 variants may develop gonadotroph and corticotroph deficiencies up to adulthood [19]. The Great Ormond Street Hospital cohort proposed a phenotype-guided genetic analysis flowchart [44], and the Italian review recommended ordering the genes by hormonal and imaging phenotype, extrapituitary anomalies and frequency in the reference population [41].

Copy number changes carry particular weight: SOX3 duplications and rearrangements are detected by chromosomal microarray (CMA) or genome and may escape the exome; the 1q25 microdeletion with LHX4, the 14q22-q23 deletions with BMP4, OTX2 or SIX6, the 20p11.2 deletions with FOXA2 and whole-gene PROP1 deletion require CNV methods [22, 40, 49, 79, 91]. Serial genetic re-evaluation (panel and then exome) allowed the diagnosis of LHX3 deficiency seven years after a negative panel [96].

In the British cohort, variants were found in GH1/GHRHR (51/414 screened), PROP1 (17/253), POU1F1 (15/139), SOX2 (13/59), SOX3 (9/354), LHX3/LHX4 (8/110), HESX1 (8/724), GLI2 (7/106), OTX2 (5/59) and SHH (2/64), and NGS identified 26 novel variants in 35 patients from 24 families [44]. In the Czech cohort with clinical GH deficiency, CPHD was present in 46% of patients with genetic GH deficiency, against 4% of those with an alternative aetiology and 12% of those who remained without a cause [128].

5.9. Test limitations and report content

The proportion of pathogenic PROP1 variants detectable is more than 98% by sequencing and less than 2% by deletion/duplication testing, according to the Human Gene Mutation Database (HGMD); this figure describes the known mutational spectrum and not clinical sensitivity, because the overall test yield in CPHD varies between 10 and 35% depending on the cohort [4, 18, 44]. Exome sequencing does not reliably detect SOX3 duplications, structural variation, deep intronic variants or low-level mosaicism; apparent homozygosity may correspond to a deletion of one or more exons on the other allele (false homozygosity) or to uniparental isodisomy [4, 49]. Parental mosaicism has been documented in OTX2 and, in GH deficiency, a mother apparently heterozygous by Sanger had 30% of the mutant allele in blood and saliva by NGS, which justifies preferring NGS when testing the parents [23, 95]. GLI2 missense variants and many heterozygous HESX1 and LHX4 variants are difficult to interpret, and a negative result does not exclude a genetic cause, given that most patients remain without a molecular diagnosis [17, 50, 71]. The report should state the gene, the versioned reference transcript (MANE Select: PROP1 NM_006261.5, POU1F1 NM_000306.4, HESX1 NM_003865.3, LHX3 NM_178138.6, LHX4 NM_033343.4, OTX2 NM_021728.4, SOX3 NM_005634.3, GLI2 NM_001374353.1, ROBO1 NM_002941.4, RNPC3 NM_017619.4, FOXA2 NM_021784.5, NFKB2 NM_001322934.2, EIF2S3 NM_001415.4), the HGVS c. and p. nomenclature, zygosity, the ACMG/AMP class and, for VUS, the recommendation for segregation studies [4, 93]. In an AR gene, a single pathogenic variant does not establish the diagnosis [95].

5.10. Practical algorithm

5.11. Prenatal and preimplantation diagnosis

When the family variants have been identified, prenatal diagnosis and preimplantation genetic testing (PGT) are possible; perspectives on prenatal diagnosis of a treatable disorder differ between professionals and families [4]. In TBX19 deficiency, a differential diagnosis, siblings can be tested before or at birth so that hydrocortisone can be started immediately [69]. Ultrasound does not allow diagnosis of isolated CPHD; in syndromic forms, the associated malformations (polydactyly, anophthalmia, HPE, heart disease) can be detected during pregnancy, and GLI2-related HPE9 has antenatal onset in the Orphanet classification [35].

6. Differential Diagnosis

6.1. Comparative table

6.2. Main differential diagnoses

The first differential is between CPHD and IGHD, and it is a dynamic boundary. In the Spanish cohort of 30 children with initial IGHD and a pituitary morphological anomaly, six progressed to CPHD after a median of five years of follow-up, with TSH as the most frequent additional deficiency (80%) followed by gonadotrophins [105]. In the Polish series of 50 children with PSIS, 32 had an initially isolated deficiency and 15 of these (47%) developed additional deficiencies, so the proportion with CPHD rose from 32% to 62% [109]. GH1-related IGHD type II may also progress to CPHD [4]. An isolated deficiency therefore does not exclude a developmental gene, and surveillance of the other axes continues.

The second differential is isolated deficiency of one axis mimicking CPHD. TBX19 causes severe isolated neonatal ACTH deficiency, with hypoglycaemia, seizures, cholestasis and frequent neonatal deaths in the family; all the other axes are normal and MRI is normal; variants were found in 65% of patients with complete neonatal-onset deficiency and in none of those with partial or late-onset deficiency; the founder variants are c.840del in northern Morocco and p.(Gln28Ter) in Finland; the hydrocortisone dose of the reported patients was about 15 mg/m²/day, against about 8 mg/m²/day in the Endocrine Society guideline for paediatric adrenal insufficiency, and there is no need for a mineralocorticoid [69]. IGSF1 deficiency is the most common genetic cause of central hypothyroidism and is associated with PRL deficiency in 61% and transient childhood IGHD in 16% of men, with adult macro-orchidism and a late pubertal rise in testosterone; one third of female carriers have central hypothyroidism, and in adulthood there is somatotroph hyperfunction [130]. A child with central hypothyroidism and low PRL may therefore have IGSF1 rather than POU1F1 deficiency: macro-orchidism and X-linked inheritance distinguish the two [68, 130].

The third differential is isolated hypogonadotropic hypogonadism, which shares genes with CPHD (PROKR2, FGFR1, FGF8, CHD7, SOX2, SOX3) and may progress to it [4, 25]. In PROP1 deficiency, gonadotrophin deficiency may be the presentation and GH and TSH deficiencies may appear only in adulthood [71, 92], which justifies periodic assessment of GH and FT4 in cases of familial central hypogonadism without a molecular diagnosis. The fourth differential is a sellar mass: PROP1 hyperplasia can mimic adenoma, craniopharyngioma or Rathke's cleft cyst and lead to unnecessary surgery, which a molecular diagnosis avoids [24, 71]. Finally, short stature with a low GH peak is not always GH deficiency: in the Czech cohort, 26 of the 39 genetic diagnoses were alternative aetiologies (13 RASopathies and 8 growth plate dysplasias), with GH peaks, CPHD and MRI anomalies less frequent than in genetic GH deficiency [128].

7. Treatments and Risk Management Strategies

7.1. General principles

Treatment is replacement of each deficient axis under endocrine supervision, with lifelong follow-up and a multidisciplinary team in the syndromic forms [4, 117]. No medicine is approved specifically for a genetic form of CPHD: eligibility derives from the documented hormone deficiency and not from the genotype, and there is no ClinGen actionability assertion for PROP1, LHX4 or SOX3 [21, 22, 49, 67]. Three rules of order run through the entire treatment. The first is to treat cortisol deficiency before starting levothyroxine, because levothyroxine increases cortisol clearance and can precipitate an adrenal crisis; if central adrenal insufficiency cannot be excluded, the glucocorticoid is started before levothyroxine [4, 17, 25, 27]. The second is that GH can unmask adrenal insufficiency and central hypothyroidism, so FT4 and the corticotroph axis are reassessed after starting or adjusting GH [94, 106, 107]. The third is to use the lowest safe dose of hydrocortisone in the growing child, so as not to interfere with the response to GH [4]. As to doses, the reference is that of the guidelines (PNDS, SBEM, ETA, Endo-ERN, BSPED, GRS, European consensus on hypogonadism) for GH, hydrocortisone, levothyroxine, desmopressin and sex steroids; the EMA or FDA label and the Portuguese SmPC are given for comparison, and the difference is flagged in the tables in a dedicated column.

7.2. Emergency: hypoglycaemia and adrenal crisis

When adrenal crisis is suspected, investigations should not delay hydrocortisone [106]. The British Society for Paediatric Endocrinology and Diabetes (BSPED) published in 2023 a consensus of 16 experts, reviewed by the Society for Endocrinology and by patient associations, which applies to primary and secondary adrenal insufficiency, including hypopituitarism, in those under 18 years [26]. At a first presentation, urea and electrolytes, glucose, ACTH, cortisol, renin, aldosterone and 17-hydroxyprogesterone are sampled before hydrocortisone, without delaying it [26]. In secondary insufficiency, cortisol deficiency reduces free water clearance and contributes to hyponatraemia, and some fluid restriction may be appropriate [26].

The French PNDS uses, in a child's crisis, hydrocortisone hemisuccinate 1–2 mg/kg every 6–8 h by the IV, IM or subcutaneous (SC) route, with hydration of 150–180 mL/kg/day in the newborn and 2.5–3 L/m²/day in the child, in 5% glucose (10% for hypoglycaemia) with sodium chloride 10–15 mEq/kg/day; in the adult, 100 mg IM or IV followed by continuous infusion of 100 mg/24 h and 1 L of normal saline in the first hour; and, on the emergency card for pre-hospital IM or SC injection, 25 mg below 1 year, 50 mg between 1 and 6 years and 100 mg (or 50 mg repeated after 15 minutes) from 6 years and in the adult; in minor surgery or fasting in the child, 1 mg/kg IV every 6 h not exceeding 25 mg per dose, and in adult surgery 100 mg on the day of the procedure followed by 100 mg/24 h or 25 mg every 6 h [19]. The labels of injectable hydrocortisone, cited for comparison, are as follows: the Portuguese Summary of Product Characteristics (SmPC) for injectable hydrocortisone (100 mg, powder for solution for injection) indicates acute adrenal insufficiency with an initial dose of 100 to 500 mg IV or IM, repeatable every 2, 4 or 6 h, and in paediatrics a reduction according to severity and response, never less than 25 mg/day [133]; the Food and Drug Administration (FDA) label for Solu-Cortef® has the same initial regimen and a paediatric range of 0.56–8 mg/kg/day (20–240 mg/m²/day) in three or four doses, without specific doses for paediatric adrenal crisis [134]. The age- or weight-based doses of the BSPED and the PNDS (for example, 25 mg below 1 year) are the reference doses; they fall within the paediatric range of the FDA label, although they are not written in any label. In persistent hypoglycaemia of the newborn with GH deficiency, daily rhGH from the neonatal period helps to correct the hypoglycaemia and may improve cholestasis [17]. Glucagon is approved for severe hypoglycaemia in the context of diabetes (emergency kit: 0.5 mg below 25 kg or 6 years and 1 mg above; nasal glucagon Baqsimi® 3 mg from 1 year in the USA); its use in hypopituitarism is an extrapolation, the response to glucagon is variable in endocrine disorders and the neonatal dose is not stated in the labels [108, 135, 136].

7.3. Maintenance glucocorticoid and sick-day rules

Hydrocortisone is the glucocorticoid of choice. The reference doses are those of the guidelines, described below; the labels and SmPCs, cited for comparison, indicate 8–10 mg/m²/day in three doses in the child with Alkindi® (EU and FDA), 12–20 mg/m²/day in the child and 20–40 mg/day in the adult with Hidrocortisona Roussel® (Portuguese SmPC), 15–25 mg/day after growth with Efmody® and 20–30 mg/day with Plenadren® [137–141]. Physiological cortisol production in the preterm infant is about 7 mg/m²/day on the fifth day and 6 mg/m²/day in the second week [17]. The recommended maintenance doses are about 8 mg/m²/day in 3–4 doses in the BSPED, 8–10 mg/m²/day in 2–3 doses in the PROP1 GeneReviews and in the European SmPC and FDA label for Alkindi®, and 9–12 mg/m²/day in 3–4 doses as the starting dose in the newborn with hypopituitarism (above the Alkindi® range) [4, 17, 26, 137, 138]. In the adult, the Brazilian guideline recommends 15–20 mg/day in 2–3 doses (below the 20–40 mg/day of the Portuguese SmPC) (the largest on waking) and advises against prolonged maintenance of more than 20 mg/day of hydrocortisone or equivalent, because of the metabolic profile, cushingoid morbidity and mortality [106]. The French PNDS recommends 8–10 mg/m²/day in the child, with higher doses per body surface area in the youngest, in two or, preferably, three doses; with the 10 mg tablets available in France, it suggests a quarter tablet (2.5 mg) twice daily below 6 years and increases in 2.5 mg steps, or a hospital-prepared oral suspension of 1 mg/mL; in the adult, 10–20 mg/day in 2–3 doses, the largest in the morning (also below the Portuguese SmPC); prednisolone and dexamethasone only after expert advice; and it does not recommend prolonged-release hydrocortisone preparations, because they are not reimbursed in France [19]. A mineralocorticoid is unnecessary in secondary insufficiency [106, 139].

Sick-day rules differ between sources. The BSPED recommends, with fever, flu, infection or illness that prevents school attendance, a total dose of about 30 mg/m²/day in four equal doses throughout the illness, instead of doubling or tripling, to standardise the dose regardless of the cause; no change for a mild cold without fever and minor bruises; with vomiting or diarrhoea, continue orally if the dose is retained for 30 minutes and, if not, IM injection and an emergency call; consider one or two sick-day doses after vaccinations; on long flights, the usual morning dose every 6–8 h [26]. The labels, for comparison, indicate doubling or tripling the dose in mild illness and switching to the parenteral route in severe illness (Alkindi®, Hidrocortisona Generis®) [137, 142]. The French PNDS combines the two approaches: doubling or tripling, which in the child corresponds to 30 mg/m²/day in 3–4 doses and in the adult to 60 mg/day in 3–4 doses, with IM or SC injection if vomiting persists [19]. The GeneReviews, the Alkindi® SmPC and the Brazilian guideline retain doubling or tripling in mild illness and the parenteral route (50–100 mg with fluids in GeneReviews) in severe illness or surgery [4, 106, 137]. Education, the emergency card, the bracelet and the injection kit are part of treatment; in Brazil, the Associação Brasileira Addisoniana distributes educational material and emergency kits [26, 106]. Compounded hydrocortisone preparations are not recommended in Brazil, owing to uncertainty about origin, storage and bioequivalence [106].

7.4. Levothyroxine in central hypothyroidism

Levothyroxine is the treatment of central hypothyroidism, and T3 is not recommended [106]. The reference doses are those of the guidelines (Endo-ERN, ETA, PNDS, SBEM); the FDA label and the Portuguese SmPCs are given for comparison, in the last rows of the table. Titration is by FT4 and not by TSH: the FDA label for Synthroid® states that, in secondary or tertiary hypothyroidism, TSH is not a reliable measure of dose adequacy and should not be used, and that FT4 should be restored to the upper half of the reference range [125]. The Endo-ERN initiative recommends keeping FT4 above the mean or median of the range for age, omitting TSH if it was low before treatment and not interpreting a low TSH as overtreatment [27], and the Brazilian guideline sets the target in the upper half with sampling before the dose [106]. The Portuguese SmPC for Eutirox® states that basal TSH “provides a more reliable basis for maintenance of treatment”, a sentence written for primary hypothyroidism that does not apply to central hypothyroidism [143].

The PROP1 GeneReviews indicates 1–3 µg/kg/day [4]. The French PNDS sets the target in the upper half of the FT4 range and allows, when TSH is inappropriate for FT4 at diagnosis (normal or moderately elevated), a TSH below 1 mU/L to be used as an additional target [19]. In the newborn, the tablet is crushed and mixed with water, breast milk or formula, or a solution is used; iron, soy, calcium and anticonvulsants reduce absorption, and without an enteral route intravenous T3 can be used at 75% of the total oral levothyroxine dose [17]. With congenital heart disease and imminent heart failure, the starting dose is about 50% of that recommended [27]. A 2026 study in 33 children with IGHD found no change in TSH, free T3, FT4, ACTH or cortisol 3–6 months after starting somatrogon, and the authors stress that the effects of long-acting GH in patients with multiple deficiencies remain to be clarified [145]. The ETA recommends increasing levothyroxine when introducing GH, oestrogen or oral contraceptives, at puberty, during ovarian stimulation, in pregnancy and with weight gain, with FT4 and TSH 4–6 weeks later [25]; the Brazilian guideline requests FT4 6 weeks after starting GH [106]. Levothyroxine is contraindicated in uncorrected adrenal insufficiency [125].

7.5. Daily somatropin

rhGH (somatropin) is started as soon as the deficiency is identified, with a weight-based dose that increases with weight up to the maximum at puberty [4]. The labels and SmPCs in the following table are given for comparison with the reference dose of the GRS, which recommends an individualised dose, the lowest effective, and notes that the most severe deficiency (low peak, low IGF-I, additional deficiencies, abnormal MRI or a genetic cause) responds to lower doses, of 17–35 µg/kg/day (0.16–0.24 mg/kg/week; about 0.7–1.0 mg/m²/day) [115]. Adjustment is mainly by growth velocity and the change in height score every 6–12 months, with annual IGF-I and a target close to 0 SD; a 20% dose adjustment corresponds to about 1 SD of IGF-I; an inadequate response in the first year is defined as an increase in velocity of less than 2 cm/year, a velocity below 0 SD or a gain in height score of less than 0.3 SD per year [115].

The French PNDS recommends starting at the lower end of the 25–35 µg/kg/day range of the marketing authorisations (25 µg/kg/day) and adjusting by response and IGF-I (the Portuguese SmPC for Genotropin® defines no maximum dose for childhood GH deficiency; the 2.7 mg/day limit refers to Prader-Willi syndrome) [107]; in the newborn the indication is urgent, to treat hypoglycaemia, with very small doses (0.1–0.2 mg/day), possibly in two daily injections (a regimen with no counterpart in the label); in obesity, the dose is calculated from ideal weight for height; and it does not recommend routinely increasing the dose at puberty [19]. The same document considers the auxological criteria (height below −2 SD, velocity below −1 SD) inappropriate for deferring treatment in multiple deficiency with abnormal MRI, in which the initial objective is metabolic and neurodevelopmental, and proposes IGF-I 3–6 months after starting and then every 6–12 months, in the same laboratory [19]. Starting doses differ by region: 25 µg/kg/day in most of Europe, Canada and Japan, 4.5 mg/m²/week in Australia and up to 43 µg/kg/day in the USA [115]. In Brazil several somatropins are registered, including Genotropin®, Norditropin®, Omnitrope®, Saizen®, Hormotrop®, Criscy®, Biomatrop®, Eutropin® and the Bio-Manguinhos somatropin, and Ministry of Health ordinance no. 28 of 30 November 2018 approves the Clinical Protocol and Therapeutic Guidelines for Hypopituitarism, which regulates GH in the Unified Health System (SUS) in children and adults [106, 155]. The labels and SmPCs warn of intracranial hypertension (fundoscopy before and periodically), slipped capital femoral epiphysis, progression of scoliosis, glucose intolerance, progression of neoplasms, the appearance or worsening of hypothyroidism and the unmasking of hypoadrenalism, with the need to increase the glucocorticoid in patients already treated [107, 150, 152]. An insufficient response in the first year requires assessment of adherence, hypothyroidism, undernutrition, advanced bone age and anti-GH antibodies [150].

The PES (2016) recommends weight- or body surface area-based doses (strong) and a starting dose of 0.16–0.24 mg/kg/week (22–35 µg/kg/day), individualised thereafter and higher in some patients (strong, low-quality evidence), favouring the lowest dose with demonstrated efficacy [120]. It does not recommend titration by IGF-I, owing to the lack of adult height data, but suggests measuring it to monitor adherence and the response to dose changes and lowering the dose if it exceeds the laboratory range for age or pubertal stage (conditional, very low-quality evidence); it does not suggest three-times-weekly administration [120]. It recommends not routinely increasing to 0.7 mg/kg/week at puberty (strong), a dose approved by the FDA on the basis of a trial in which 4 of 48 patients in the high-dose arm had effects compatible with GH excess, and not continuing the paediatric dose after growth velocity falls below 2–2.5 cm/year, with an individual decision to stop earlier (strong) [120]. In KIGS (1,258 patients with GH deficiency), patients with multiple deficiency reached a mean adult height of −0.7 SD in men and −1.1 SD in women, with a difference from target height of −0.4 and −0.8 SD, on a mean dose of 0.18 mg/kg/week; for comparison, adult height in untreated idiopathic IGHD averaged −4.7 SD (−3.9 to −6 SD) [120]. On safety, the PES recommends advance information and, at each visit, history and examination directed at intracranial hypertension, slipped capital femoral epiphysis and progression of scoliosis (strong): intracranial hypertension occurs in about 28 per 100,000 treatment-years, more in organic deficiency, usually at the start or after a dose increase, reverses with withdrawal and justifies fundoscopy by an ophthalmologist in the presence of severe headache, visual disturbance or vomiting; slipped epiphysis occurs in 73 per 100,000 treatment-years (18.3 in IGHD; 86.1 in intracranial tumours; 120 in craniopharyngioma), at a median of 0.4–2.5 years after starting; scoliosis affects about 0.2% of treated children with IGHD or idiopathic short stature [120]. It suggests not performing routine cardiac assessment, absorptiometry or lipid profile in the treated child (conditional), focusing glucose surveillance on patients at higher risk of diabetes and informing about the uncertainty of safety after treatment [120].

7.6. Long-acting growth hormone

Three weekly long-acting GH preparations (LAGH) are approved in several countries: lonapegsomatropin (Skytrofa®; a prodrug with transient pegylation, half-life 25 h), somapacitan (Sogroya®; a point mutation with non-covalent albumin binding, about 34 h) and somatrogon (Ngenla® in the EU and the USA, Genryzon® in Brazil; fusion with three carboxy-terminal peptides of hCG, 37.7 h) [155, 156].

In the adult, somapacitan is started at 1.5 mg/week (1 mg from 65 years; 2 mg with oral oestrogen in the USA; in the EU, 2 mg/week when switching from daily GH and 4 mg with oral oestrogen), titrated every 2–4 weeks up to 8 mg/week, and lonapegsomatropin at 1.4 mg/week between 30 and 60 years without oral oestrogen, 2.1 mg/week below 30 years or with oral oestrogen and 0.7 mg/week above 60 years, up to 6.3 mg/week [157, 159, 160]. Two recommendations bear directly on CPHD. The 2026 GRS consensus considers that patients with congenital deficiency, severe deficiency or multiple pituitary deficiencies need an individualised dose, that label doses may be excessive in severe deficiency or in panhypopituitarism requiring low daily doses (the individualised dose is the reference, and the label dose serves for comparison), and that in infants and very young children with severe deficiency, especially with a history of hypoglycaemia or multiple deficiencies, fasting hypoglycaemia at the end of the dosing interval should be monitored, with explicit instructions to the family [164]. The 2025 international paediatric consensus, funded by Pfizer, notes that few patients under 3 years entered the trials, that the risk of hypoglycaemia may increase 1–2 days before each injection and that the impact of LAGH on glucocorticoid and levothyroxine doses is unknown [156]. In France, at the time of the September 2026 expert review, somapacitan was the only LAGH approved in children and adults [165]. In Brazil, Sogroya® (2023) and Genryzon® (2022) are registered, and no registration of lonapegsomatropin was found [155].

7.7. Gonadotroph axis: micropenis, cryptorchidism, puberty and fertility

Treatment of the gonadotroph axis in CPHD follows that of congenital hypogonadotropic hypogonadism, whose 2015 European consensus applies by extrapolation from an analogous condition [126]. Paediatric doses of testosterone and oestradiol are largely off-label: the Portuguese SmPC for Testoviron Depot® (testosterone enanthate 250 mg/mL) states that it is not indicated in children and adolescents, the FDA label for the cypionate does not establish safety below 12 years, and pubertal induction doses with oestradiol are not stated in any label [166–168]. The other Portuguese SmPCs consulted confirm this situation: Nebido® (testosterone undecanoate 1,000 mg every 10–14 weeks, with a minimum first interval of 6 weeks) is not indicated below 18 years, and Sustenon® (250 mg every 3 weeks) and Testogel® (50 mg/day, maximum 100 mg/day) have no established safety in minors; Dermestril® (patches of 25, 50 and 100 µg/24 h applied twice weekly), Estrofem® and Zumenon® (oral oestradiol) are indicated only for postmenopausal hormone replacement therapy, and Zumenon® states that it has no paediatric indication; oral Utrogestan® is indicated, as an adjunct to oestrogen in the menopause, at 200 mg/day for 12–14 days per month [169–175]. Pubertal induction and oestrogen replacement in the young woman with hypopituitarism are thus off-label in Portugal. The reference doses are those of the progressive regimens of the European consensus and the PNDS (50 mg/month) and of GeneReviews (100 mg/month); the only paediatric label regimen identified, cited for comparison, is that of testosterone enanthate for delayed puberty in the USA (50–200 mg every 2–4 weeks for 4–6 months), from which these regimens differ [4, 19, 126, 176].

Testosterone does not induce gonadal maturation or fertility, and an increase in testicular volume on testosterone requires the diagnosis to be reconsidered, because spontaneous reversal occurs in 10–20% of congenital hypogonadotropic hypogonadism [126]. In women with hypopituitarism on GH, the Brazilian guideline recommends transdermal oestrogen, because oral oestrogen antagonises the hepatic action of GH, and notes that hypopituitarism removes the female vascular advantage, so replacement is continued in all premenopausal women [106].

Clomifene citrate is not effective in pituitary deficiency, because it requires a functioning pituitary; GeneReviews recommends gonadotrophins and not clomifene in PROP1 deficiency [4, 106]. The French PNDS allows clomifene as first line only in partial hypogonadotropic hypogonadism and recommends LH and FSH in complete deficiency [19]. For spermatogenesis, it uses highly purified urinary gonadotrophins or recombinant FSH with recombinant hCG (choriogonadotropin alfa, prescribed in France under a temporary recommendation for use since March 2021, because extracted hCG ceased to be available), with sperm in the ejaculate in 75% of cases after 3–19 months, and recommends sperm cryopreservation before testosterone is resumed [19]. GH deficiency is associated with lower pregnancy rates in some studies and should be treated beforehand [106]. In ovulation induction with gonadotrophins in hypopituitarism, pregnancy rates were 47–76%, against more than 81% in isolated hypogonadotropic hypogonadism, with many cancelled cycles, live births in about 42–79% and a trend towards worse outcomes with childhood onset; in a series of five women with childhood-onset CPHD, all became pregnant with stimulation and insemination or in vitro fertilisation (IVF) in 1–5 cycles [181]. Low anti-Müllerian hormone (AMH) does not indicate diminished ovarian reserve in hypogonadotropic hypogonadism [126]. Women with RNPC3 variants have primary ovarian insufficiency and do not fit this reasoning [61]. The hCG doses in the FDA labels for cryptorchidism (for example, 4,000 IU three times per week for three weeks) and for male hypogonadotropic hypogonadism (500–1,000 IU three times per week or 4,000 IU three times per week for 6–9 months) are regimens “advocated by various authorities” and not specific to CPHD [182].

7.8. Desmopressin and arginine vasopressin deficiency

In the newborn, the recommended management of AVP-D is fluid therapy alone; very severe central AVP-D may require desmopressin, with a low starting dose (for example, 1 µg), monitoring of electrolytes, osmolalities and weight and an escape diuresis before each dose, because overtreatment (water retention, hyponatraemia, cerebral oedema) is more dangerous than undertreatment; in newborns with ACTH deficiency who vomit their hydrocortisone, desmopressin is withheld until glucocorticoid cover is available [17]. In the child and the adult, the Portuguese SmPC for oral lyophilisate Minirin® indicates a starting dose of 0.06 mg three times daily, maintenance of 0.06–0.12 mg three times daily and a usual total dose of 0.12–0.72 mg/day, the same in paediatrics [183]. In the USA, the tablets start at 0.05 mg twice daily (0.1–1.2 mg/day in 2–3 doses; safe from 4 years), the nasal spray at 10 µg daily from 4 years (up to 30 µg in the child and 40 µg in the adult) and the injection at 2–4 µg/day, with efficacy established only from 12 years [184–186]. The “escape method”, with periodic omission or delay of a dose until diuresis occurs, reduces hyponatraemia [64]. The reference doses are those of the PNDS (starting dose of 60 µg twice daily; 1–2 µg/kg/day of divided lyophilisate in the child) and, in the newborn, the starting dose of about 1 µg; the Portuguese SmPC, for comparison, indicates 0.06 mg three times daily, the same in the child [17, 19, 183]. The French PNDS describes the forms of Minirin® (solution for injection 4 µg/mL, nasal spray 2.5 or 10 µg per dose, oral lyophilisate Minirinmelt® 60, 120 or 240 µg) and the adult doses (1–2 µg once or twice daily by injection, 5–20 µg two to three times daily by the nasal route, 60–120 µg two to three times daily as lyophilisate, starting at 60 µg twice daily and increasing the evening dose until nocturia disappears); in the child it starts with 1–2 µg/kg/day of divided lyophilisate (cut or dissolved in a minimal volume of water in the newborn), under strict monitoring of urine output, weight and serum sodium, and requests an electrolyte panel at least every six months; in hypothalamic adipsia it proposes a fixed dose twice daily with a fluid intake volume defined by reference weight [19].

7.9. Particular features by gene

In PROP1 deficiency, surveillance of the adrenal axis is lifelong and the pituitary mass should not be operated on [4, 24]. In POU1F1 deficiency, the corticotroph and gonadotroph axes are usually preserved and are not routinely treated with glucocorticoid or sex steroids, but they are tested at diagnosis and periodically; PRL deficiency is not replaced, but it is documented because it predicts inability to breastfeed [68]. In LHX3 deficiency, replacement is combined with orthopaedic (cervical rigidity, scoliosis) and audiological follow-up with hearing aids [21]. In OTX2 deficiency and the forms with ocular anomalies, ophthalmology manages the orbit, refraction, amblyopia and retinal dystrophy [23]. In DAVID syndrome, the adrenal axis is assessed at diagnosis and periodically, including carrier relatives, and hydrocortisone and GH are used according to the deficiencies [30]. In FOXA2 disorders, hyperinsulinism is treated according to the 2024 international guideline [40]. In Pallister-Hall syndrome, cortisol deficiency is the most urgent, biopsy or resection of the hamartoma should be avoided and many survivors needed levothyroxine, GH and glucocorticoid from early on and intravenous glucose in the neonatal period [16, 100]. In SOX3 duplication, levothyroxine followed by rhGH took a boy from −5.87 to −1.78 SD in two years [49]. In RNPC3 deficiency, two men grew normally without GH despite severe biochemical deficiency, which shows that the decision to treat is also based on growth [61]. In TBX19 deficiency (differential diagnosis), the reported hydrocortisone dose is about 15 mg/m²/day [69].

7.10. Interactions between replacements and agents to avoid

7.11. Comparative regulatory status

7.12. Main clinical trials

None of the GH trials was designed for genetic CPHD, and the sources consulted do not state the proportion of patients with multiple deficiencies included; the results measure efficacy in GH deficiency in general, in a population of treatment-naive prepubertal children. The trials compare each LAGH with daily GH, and there are no head-to-head trials between LAGH preparations, so the numerical differences between trials do not allow the products to be ranked. The negative trials count: somatrogon failed its outcome in adults and macimorelin failed as a paediatric test. The effect of setmelanotide was measured in acquired hypothalamic obesity, and extension to the congenital form depends on the ongoing trial. The October 2026 ClinicalTrials.gov search found no therapeutic trials specific to genetic CPHD apart from the setmelanotide substudy, and no gene therapy trials; a negative search does not prove the absence of studies [196].

7.13. Developments in the last 12 months

The organoid study is preclinical and the authors indicate as next steps non-clinical data for a first-in-human trial, immunosuppression and production with clinical-grade cells [197]; human organoids have already served to clarify the mechanisms of OTX2 and NFKB2 [97]. A 2026 commentary on CRISPR interference in HESX1 haploinsufficiency presents no experimental data of its own [198].

7.14. Pregnancy, lactation, perioperative care and transition

Pregnancy. There are no evidence-based guidelines for hypopituitarism in pregnancy, and outcome data in women with genetic CPHD are scarce [181]. GH is stopped when pregnancy is confirmed, because placental GH replaces it from the fifth week; alternatives have been proposed (keeping the dose in the first trimester, halving it in the second and stopping at the start of the third, or adjusting by IGF-I), without validation in trials [181]. Hydrocortisone is the glucocorticoid of choice because it is inactivated by placental 11-beta-HSD2, with a 20–40% increase in the third trimester and at least quarterly monitoring; at delivery, 50 mg IV in the second stage of labour, or 100 mg IV before caesarean section followed by continuous infusion or boluses every 6–8 h; post partum, double for a few days and return to the previous dose within about a week [181]. Levothyroxine shows the most marked divergence between sources: the ETA recommends increasing it in pregnancy and the Endo-ERN initiative targeting an FT4 above the mean of the trimester-specific range [25, 27]; the Brazilian guideline considers that, as a rule, the 20–50% increase of primary hypothyroidism is not needed in central hypothyroidism, because the thyroid responds to hCG [106]; and the French PNDS proposes increasing levothyroxine by 30% as soon as pregnancy is diagnosed, with FT4 every 4–6 weeks [19, 181]. Recent series of panhypopituitarism describe mean increases of 71.7–100% [181]. The PNDS further recommends increasing hydrocortisone by 30% in the third trimester and injecting 100 mg at delivery, not measuring cortisol during pregnancy (values rise physiologically), considers it unnecessary to continue GH, warns that desmopressin may need to be increased from the first trimester (it is not degraded by placental vasopressinases) and that AMH is underestimated in hypogonadotropic hypogonadism, and cites cumulative pregnancy rates of 45–100% after induction of folliculogenesis in this condition, with few series of women with combined deficiencies [19]. The complications described include miscarriage, fetal malpresentation, a small-for-gestational-age newborn and postpartum haemorrhage, and caesarean sections occurred in about 60% in the series [181].

Lactation. PRL deficiency prevents breastfeeding in PROP1 and POU1F1 deficiency: two women with PROP1 deficiency became pregnant after ovulation induction without GH and could not breastfeed, and the patient in the clinical case had agalactia despite breast enlargement [68, 181, 199]. Counselling before delivery allows alternative feeding to be planned [181]. There is no commercial treatment for PRL deficiency [17].

Perioperative care. In the child, minor surgery under local anaesthesia requires a sick-day dose beforehand; major surgery (more than 90 minutes) requires IV hydrocortisone at induction (2 mg/kg, maximum 100 mg; 4 mg/kg in the newborn) and a 24 h weight-based infusion (up to 10 kg 25 mg; 10.1–20 kg 50 mg; 20.1–40 kg 100 mg; 40.1–70 kg 150 mg; more than 70 kg 200 mg), or boluses of 2 mg/kg every 6 h intraoperatively and of 1 mg/kg (maximum 50 mg) every 6 h postoperatively; the patient should be first on the operating list, with fasting of up to 6 h and fluids containing sodium chloride and glucose [26]. GeneReviews indicates 50–100 mg parenterally with fluids in major illness and surgery [4].

Transition. In patients with childhood-onset GH deficiency and a proven genetic cause, embryopathic lesions with multiple deficiencies or irreversible structural lesions, the Endocrine Society dispenses with GH retesting after adult height is reached, and a low IGF-I at least one month off GH documents persistent deficiency; idiopathic IGHD or IGHD with a single additional deficiency should be retested [124]. The Portuguese SmPC for Norditropin® dispenses with re-evaluation in patients with more than three deficiencies, a defined genetic cause or structural anomalies if IGF-I is below −2 SD after 4 weeks without treatment, and that for Genotropin® accepts the same criterion in congenital causes [107, 146]. The PES (2016) recommends considering GH deficiency persistent, without retesting, with three or more pituitary deficiencies of any cause, with a documented causal variant or with a specific hypothalamic–pituitary structural defect, except EPP (strong); in these patients test failure approaches 100%, IGF-I off GH is unnecessary and may even be normal in multiple deficiency, so a normal IGF-I does not exclude persistent deficiency [120]. It recommends reassessing the axis, after at least one month off GH, when there is only one additional deficiency, idiopathic IGHD, IGHD with a small pituitary or EPP, and after irradiation (strong), starting with IGF-I (conditional) and proceeding to a stimulation test if IGF-I is low (strong); in idiopathic IGHD with IGF-I above 0 SD testing is unnecessary [120]. EPP with stalk agenesis is associated with persistent deficiency, whereas with a normal stalk retesting tends to be normal; in a small study, patients with EPP and a normal retest had a peak below 5 µg/L and a worse lipid profile 2 years later, so the PES advises following these patients and repeating the assessment more than once during transition; a small pituitary does not count as a structural defect, because many of these patients retest normal [120]. During transition, the ITT with a cutoff of 5.6 µg/L (immunometric assay) had a sensitivity of 77%, a specificity of 93% and correct classification of 87%, and the PES suggests offering GH for persistent deficiency (conditional), with the caveat that the trials used doses between 12.5 and 25 µg/kg/day or a fixed 200 µg/day and that the optimal dose is not defined [120]. The French PNDS dispenses with retesting in severe multiple deficiencies (three or more lineages), with or without EPP, in identified genetic causes (pituitary development transcription factors, GHRHR, GH1, POU1F1, PROP1) and in midline cerebral or craniofacial anomalies, and reassesses the gonadotroph axis after puberty, with sex steroids withheld for 1–3 months; it defines transition as the period from the end of growth until about 6–7 years later [19]. GH continues after final height to complete skeletal and muscle maturation, because 95% of peak bone mass is acquired by the mid-third decade, with absorptiometry beforehand and, if abnormal, at least every 2 years and without interruptions longer than 18 months [124]. Adult doses are 0.2–0.4 mg/day below 60 years and 0.1–0.2 mg/day above (GeneReviews), 400–500 µg/day below 30 years and higher doses during transition (Endocrine Society), or 0.4–0.7 mg/day during transition, 0.3 mg in young women and 0.2 mg in young men (SBEM), titrated to an IGF-I between the median and the upper limit [4, 106, 124]. The guideline doses are the reference; the Portuguese SmPC for Genotropin®, cited for comparison, indicates 0.2–0.5 mg/day to restart GH in the adult with childhood-onset deficiency, 0.15–0.3 mg/day with adult onset and maintenance that rarely exceeds 1.0 mg/day (0.5 mg/day above 60 years), with no defined maximum dose; the Endocrine Society starting doses below 30 years and the SBEM transition doses that exceed 0.5 mg/day exceed the restart range of the label [107]. Oral oestrogen requires substantially higher GH doses [124]. For transition on LAGH there are no data, and the principles of daily GH guided by IGF-I apply [164].

7.15. Guidelines and divergences between sources

As a rule, in each dose divergence the reference is the guideline dose, and the EMA or FDA label or the national SmPC is given for comparison (label-relation columns in 7.3, 7.4, 7.5 and 7.7). The Endocrine Society guideline for paediatric adrenal insufficiency uses about 8 mg/m²/day, whereas the reported patients with TBX19 deficiency received about 15 mg/m²/day [69]. The GeneReviews surveillance every 3–4 months is close to the PNDS visit schedule in the child (every 3–6 months) and corresponds to the practice of the reference centre that wrote it (University of São Paulo), and the guidelines for each axis propose longer intervals (section 11) [4, 25, 115].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by inheritance and scenario

8.2. Cascade testing, carriers and mosaicism

The French PNDS notes that, despite the increase in the number of known genes, fewer than 10% of patients without consanguinity or a familial form have a cause found, and that counselling is based on the mode of transmission, most often AR, and on analysis of the parents [19]. In PROP1 deficiency, both parents should be tested; detection of carriers among relatives requires the family variants to have been identified; the proband's aunts and uncles have a 50% risk of being carriers [4]. Younger siblings should have their genetic status clarified so that replacement can be started early, or, if not tested, growth surveillance [4]. In the dominant forms with incomplete penetrance, carriers identified through cascade testing are candidates for endocrine assessment and pituitary MRI, because the deficiencies may be partial and evolving [22, 50]; a child identified by polydactyly or a subtle facial difference in a family with a GLI2 variant may have unrecognised treatable hypopituitarism [50]. In DAVID syndrome, carrier relatives undergo assessment of the adrenal axis [30]. When testing the parents of an apparently de novo case, NGS detects mosaicism that escapes Sanger sequencing [95]. In Pallister-Hall syndrome, assessment of the parents, including brain MRI in some cases, informs counselling [100].

8.3. Prenatal diagnosis and preimplantation genetic testing

With the family variants identified, prenatal diagnosis and PGT are possible, and family planning is ideally undertaken before pregnancy [4]; the French PNDS considers genetic counselling at the preconception visit necessary when the genetic alteration is known [19]. The decision should take into account that isolated CPHD is treatable and that perspectives on prenatal diagnosis of treatable disorders vary [4]. In the lethal forms (biallelic LHX4) and in severe syndromic forms, the balance is different [47]. In the AD forms with incomplete penetrance, a positive prenatal result does not predict severity, because expressivity is unpredictable [46, 121]. Prenatal knowledge of a form with a risk of neonatal hypoglycaemia or adrenal crisis allows delivery to be arranged in a centre with neonatal intensive care and paediatric endocrinology, as recommended for siblings at risk of isolated ACTH deficiency [69].

8.4. Fertility of affected individuals and counselling of minors

Fertility is possible with gonadotrophins in PROP1 deficiency and in CPHD in general, and the children of a person affected with an AR form are obligate heterozygotes [4, 181]. Women with RNPC3 variants have primary ovarian insufficiency, which changes the reproductive prognosis [61]. Counselling should be offered to affected, carrier or at-risk young adults, ideally before pregnancy, and include assessment of the hereditary risks, as in the clinical case (section 10) [4, 181]. In asymptomatic minor siblings, testing for the family variant is justified by the direct benefit of starting replacement early and preventing crises [4]; the sources consulted do not specifically address carrier testing in minors.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and incidence: what each study measures

The yields of the reference cohorts (section 5.8) measure the proportion of referred patients with an identified cause, not the population frequency of the genes [22].

9.2. Geography, ancestry and founder populations

The frequency of PROP1 variants in CPHD varies from 0.8% to 64.8% depending on the country, and is higher in Eastern Europe, Russia, Portugal and Latin America, owing to the Baltic and Iberian haplotypes of c.301_302del [24, 71, 87]. POU1F1 is relatively frequent in Indian cohorts, and in the Mumbai cohort splice, intronic and frameshift variants were the most common, whereas missense and nonsense variants predominate in the worldwide spectrum (75%) [43, 68]. Recessive LHX4 deficiency was described in a Pakistani family [47]. Published PROP1 cohorts in other countries include Turkey, Morocco, Slovenia, Serbia and Germany [114, 202–206]. The lack of data from a region in the sources consulted does not demonstrate an absence of cases.

9.3. Data from Portugal and Brazil

The 2006 Portuguese multicentre study included 46 patients with CPHD (17 familial cases from 7 kindreds and 29 sporadic), selected for GH deficiency with central hypothyroidism and hypogonadotropic hypogonadism without an identified cause; PROP1 was mutated in all familial kindreds (five with c.301_302del, one with c.358C>T and one with c.2T>C, the first initiation codon variant described), and only 2 of the 29 sporadic cases (6.9%) had variants, both c.301_302del; the same variant was associated with variability in the presence and age of hypocortisolism, PRL and imaging, and one patient had a persistent sellar mass in adulthood [89]. The 2016 haplotype study had Portuguese (Covilhã) and Brazilian (São Paulo) co-authorship and showed the Iberian haplotype transmitted to Latin American patients [87].

In Brazil, a family with 10 patients homozygous for PROP1 c.301_302del, 9 born to consanguineous marriages, showed complete absence of puberty, severe pituitary hypoplasia and ACTH insufficiency in 5 of the 6 oldest patients, and a screen of 177 Brazilian patients with IGHD or CPHD found GLI2 variants in 24 [6, 13]. HC-FMUSP is the main reference centre: the PROP1 GeneReviews was written by this group [4], which described 14 patients with seven variants and frequent late diagnosis [24], the series with a eutopic posterior pituitary [91], GH1, SOX3 and TGIF1 variants [78] and, with collaborators in the USA, the EPP series with ROBO1 [101]. The 2021 guideline of the Brazilian Society of Endocrinology and Metabolism (SBEM) describes regional disparities in access to diagnosis and treatment: tetracosactide poorly available, macimorelin unavailable, oral hydrocortisone poorly available with prednisone or prednisolone as an alternative, testosterone enanthate unavailable and Plenadren® without prospect of approval; it also reports a single-centre Brazilian study of 99 adults with hypopituitarism (about half non-tumoural), with FSH/LH deficiency in 99%, GH in 98.6%, TSH in 96% and ACTH in 81.8% [106]. Only 31% of Brazilian children with GH deficiency remained deficient on retesting, and an IGF-I below 110 ng/mL had a sensitivity of 94.5% and a specificity of 100% for adult deficiency during transition [106]. The QoL-AGHDA quality-of-life questionnaire has been translated and validated for Brazilian Portuguese [106].

9.4. Special populations

Preterm newborns and infants have their own testing limitations (axis immaturity, lack of normative values), contraindication to stimulation tests below 1 year and different neonatal doses of hydrocortisone and levothyroxine [17, 26]. Young children with severe GH deficiency and multiple deficiencies on LAGH require hypoglycaemia monitoring [164]. Women with hypopituitarism on GH need transdermal oestrogen and higher GH doses with oral oestrogen [106, 124]. Adults with long-untreated congenital hypopituitarism should be followed carefully when GH is started, according to the authors of the Serbian series, in which one sibling developed glioblastoma two years after full replacement, with no causal association established [114]. In PSIS with systemic onset, neurodevelopment is worse (intellectual disability in 30.0% versus 0%), and the exploratory associations with diagnostic delay and lower FT4 and cortisol do not establish causality [20]. The elderly person with congenital CPHD needs lower doses of GH and levothyroxine [4, 25].

9.5. European reference networks and patient associations

Endo-ERN (https://endo-ern.eu/) is the European reference network for rare endocrine conditions, with a thematic group on hypothalamic and pituitary conditions, and was the initiative that produced the 2021 congenital hypothyroidism consensus [27]. In France, the FIRENDO network (https://www.firendo.fr/) and the HYPO (Marseille) and CRMERCD (Paris) reference centres are the authors of the PNDS, which lists the patient associations Grandir (www.grandir.asso.fr), Association Française du Diabète Insipide (www.diabete-insipide.fr) and Surrénales (www.surrenales.com) [19]. In Portugal, the Portuguese Society of Paediatric Endocrinology and Diabetology (SPEDP, https://www.spedp.pt/) and the Portuguese Society of Endocrinology, Diabetes and Metabolism (SPEDM, https://www.spedm.pt/) are the reference scientific societies; no specific Portuguese patient association was identified in the sources consulted. In Brazil, the Associação Brasileira Addisoniana (https://www.abaddison.org.br/) distributes educational material and emergency kits [106]. International associations include the Pituitary Foundation (United Kingdom, https://www.pituitary.org.uk/), the Child Growth Foundation (United Kingdom, https://childgrowthfoundation.org/), the MAGIC Foundation (USA, https://www.magicfoundation.org/) and the Human Growth Foundation (USA, https://www.hgfound.org/) [4]. The BSPED provides the adrenal insufficiency card and guide (https://www.bsped.org.uk/adrenal-insufficiency) [26], and the GloBE-Reg registry (https://globe-reg.net) collects patients on GH and LAGH [164]. The Orphanet page ORPHA:95494 is at https://www.orpha.net/en/disease/detail/95494 [2].

10. Illustrative Clinical Case

Pigni and colleagues published in December 2025 the case of an Italian Caucasian woman with CPHD due to homozygous PROP1 c.150del p.(Arg53AspfsTer112) (NM_006261.5), with GH deficiency, central hypothyroidism, secondary adrenal insufficiency and hypogonadotropic hypogonadism [181]. The genetic diagnosis was made at 6 years, during evaluation of growth delay, and replacement of all deficiencies allowed normal height and complete pubertal development; puberty was induced at 13 years with transdermal oestradiol patches, sequential progesterone was added after the first withdrawal bleed, about two years later, and cycles had been regular since 16 years [181].

At 26 years, after about three years of trying to conceive, she underwent multidisciplinary counselling with genetic assessment of the hereditary risks. FSH and LH were below 0.3 IU/L, AMH was normal, ovarian and uterine volumes were normal and hysterosalpingography showed bilateral tubal patency. Before pregnancy she was taking modified-release hydrocortisone 20 mg/day, levothyroxine 100 µg/day, somatropin 3.5 mg/week, transdermal oestradiol 50 µg (patch twice weekly) and micronised progesterone 100 mg/day for 14 days per 28-day cycle [181]. The first line, controlled ovarian stimulation with menotropin 37.5 to 75 IU followed by hCG and timed intercourse, failed in three cycles (the first cancelled because of poor response). In IVF, follitropin delta did not produce adequate follicular development; with recombinant follitropin alfa and lutropin alfa nine follicles were obtained and, after triggering with recombinant hCG alfa, five oocytes, one embryo and three blastocysts; the first two transfers ended in first-trimester miscarriage and the third, three months later, resulted in an ongoing pregnancy [181].

Once pregnancy was confirmed, GH was stopped in accordance with the Endocrine Society and modified-release hydrocortisone was replaced by the standard formulation three times daily (17.5 mg/day recommended, which the patient adjusted to 20 mg/day). At conception she had sodium of 140 mEq/L, potassium of 4.1 mEq/L, IGF-I of 160.3 ng/mL (107.8–246.7), FT4 of 11.7 pg/mL (9.2–16.8) and free T3 of 3.8 pg/mL (2–4.4), with 50 kg, 158 cm and a BMI of 20 kg/m² [181]. Monitoring was carried out every 2–3 weeks (free T3 and FT4, sodium and potassium, symptoms, venous blood glucose, glucometer and continuous glucose monitoring, blood pressure and weight). Hydrocortisone was increased progressively at the end of the second trimester and in the third, from 20 to 30 mg/day, because of fatigue, a trend towards lower sodium and higher potassium, still normal, and a tendency to hypoglycaemia; levothyroxine rose to 150 µg/day in the second trimester and 200 µg/day in the third, with an FT4 target in the upper half, a total increase of about 78% [181]. The oral glucose tolerance test at 26 weeks was normal, as were the electrocardiogram and echocardiogram [181]. Figure 1 of the article shows the course of free T3, FT4, weight, systolic blood pressure, sodium, potassium and blood glucose during pregnancy, with arrows at the start of hydrocortisone escalation (https://pmc.ncbi.nlm.nih.gov/articles/PMC12685998/figure/Fig1/), and Figure 2 outlines the interventions from preconception to the postpartum period (https://pmc.ncbi.nlm.nih.gov/articles/PMC12685998/figure/Fig2/); the legends were read in the full text and the figure pages opened, without visual inspection of the images [181].

Delivery was by elective caesarean section at 39 weeks, in a tertiary centre with neonatal intensive care, with IV hydrocortisone boluses of 50 mg and 100 mg and then a continuous infusion of 200 mg/24 h; on days 2 and 3 post partum two additional IV boluses were needed for moderate hyponatraemia (sodium 128 mEq/L), hypotension and fatigue, with a good response, before returning to the oral route [181]. The male newborn was healthy, weighing 3,600 g with a normal Apgar score; growth, genitalia, blood glucose, electrolytes and thyroid function were normal, and he was heterozygous for the maternal variant [181]. Post partum there was agalactia due to PRL deficiency (23 mU/L; reference 102–496) despite breast enlargement, which prior counselling had allowed to be anticipated with alternative feeding. Hydrocortisone was temporarily doubled because of fatigue and malaise, with an emergency department visit, and at 6 months it remained at double dose, without signs of overdosage, with weaning planned over more than a year (the authors consider a glucocorticoid withdrawal syndrome possible); levothyroxine reached 225 µg/day and was reduced to 175 µg/day; the oral oestrogen–progestogen was resumed one month after delivery and GH two months after [181].

The case shows the PROP1 sequence of deficiencies with fertility preserved through gonadotrophins and IVF, the need to increase hydrocortisone and levothyroxine in pregnancy, parenteral glucocorticoid cover at delivery and predictable agalactia. Some practices are specific to the centre and do not constitute routine: the 78% increase in levothyroxine exceeds the +30% proposed by the French PNDS and contradicts the SBEM position of not routinely increasing it in central hypothyroidism; the 200 mg/24 h infusion corresponds to the Society for Endocrinology adult regimen; and the prolonged weaning of hydrocortisone after delivery differs from the recommendation to return to the previous dose within about a week [19, 26, 106, 181].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The prognosis depends on the gene, neonatal severity, speed of diagnosis and prevention of adrenal crises. The most severe forms are lethal despite treatment: the siblings with biallelic LHX4 variants died in the first week [47], a truncating FOXA2 variant was lethal in a fetus [40], and in Pallister-Hall syndrome neonatal death from hypoadrenalism and death before 3 years are not rare, although prolonged survival and normal intelligence are frequent [100]. In the GOSH cohort, there were no deaths among 50 patients with multiple pituitary deficiency without septo-optic dysplasia with mortality data, 30.2% had been diagnosed in the neonatal period and all five with AVP-D had it before 4 years [127]. In septo-optic dysplasia, in a series of 88 patients with a median age of 12.4 years (0.3–36.8), there were 5 deaths, 3 from adrenal crisis and 2 from neurological problems [207]. In DAVID syndrome, 3 of the 50 patients reviewed had died and 4 developed neoplasms, a consequence of the immune defect [30]. In the adult, hypopituitarism is associated with increased cardiovascular and cerebrovascular mortality, especially in women and in those diagnosed younger, and metabolic syndrome affects about 40% [106]. According to the French PNDS, mortality in children with multiple pituitary insufficiency is increased 10-fold in infants under 2 years and 3–4-fold from childhood onwards, and the incidence of acute adrenal insufficiency in the adult is 6–8.3 episodes per 100 patients per year, with mortality estimated in 2015 at 0.5 per 100 patients per year [19]. Adrenal crises are estimated at 5–10 per 100 patient-years in Europe, with mortality of 0.5 per 100 patient-years, and about 1 in 12 adults with adrenal insufficiency will have a crisis in the following year and 1 in 200 will die of a crisis; in children, the risk factors are diagnosis at a young age, primary insufficiency, mineralocorticoid treatment and recurrent admissions, and diarrhoea and vomiting are particularly dangerous [26, 106]. Untreated crises in TBX19 deficiency cause cognitive impairment [69].

With treatment, final height approaches familial height when GH is started early: in Lithuania, the final height of 17 patients with PROP1 deficiency was −0.98 ± 1.77 SD [42]. Intelligence is normal in PROP1 deficiency [4], but in PSIS with systemic onset there was intellectual disability in 30% and the developmental quotient was associated with diagnostic delay [20]. All 17 Korean patients re-evaluated had persistent GH deficiency in adulthood and 58.9% had metabolic abnormalities [77]. In the untreated Serbian adults, two years of replacement improved bone mineral density and body composition [114]. Fertility is possible with gonadotrophins, with pregnancy rates lower than in isolated hypogonadotropic hypogonadism [181].

11.2. Progression of deficiencies

The deficiencies are progressive and cumulative, with variable degree and age at onset even within the same family [4, 118]. In PROP1 deficiency, ACTH deficiency can appear up to 63 years and adrenal function declines even after more than four decades, so surveillance of this axis is lifelong [4]. In PSIS and in IGHD with an abnormal pituitary, 30–47% develop new deficiencies after a median of about five years, with TSH first, and progression is more likely with stalk agenesis (87.5%) and with optic nerve hypoplasia [20, 105, 109]. In POU1F1 deficiency with partial transactivation, TSH deficiency may appear after GH is started [94].

11.3. Surveillance table

11.4. Transition to adult care

Transition should maintain replacement of all axes, reduce GH to adult doses without prolonged interruptions, confirm the need for GH without retesting in proven genetic causes and maintain surveillance of the corticotroph axis, whose late failure is characteristic of PROP1 deficiency [4, 124]. Patients on somatrogon need to change product, because it has no adult indication [163]. The French adult PNDS stresses that replacement is adapted to the stage of life, including pregnancy and old age, and that comorbidities, the risk of acute decompensation, fertility and quality of life require prolonged multidisciplinary care [118].

12. Summary and Final Considerations

Congenital combined hypopituitarism is a class of disorders of pituitary ontogeny in which GH deficiency is associated with at least one other anterior pituitary deficiency. Orphanet estimates the birth prevalence of non-acquired CPHD at 29/100,000 in Europe, but only a minority of patients have an identified molecular cause: about 10% in a British cohort of 1,765 patients and up to one third with exome sequencing and recent genes. The genes fall into three groups with practical consequences. The terminal transcription factors, POU1F1 and PROP1, give a pituitary with a normal stalk and posterior pituitary, a predictable hormonal signature and mainly recessive inheritance; PROP1 is the most frequent genetic cause, with founder variants of Baltic and Iberian origin widely present in Eastern Europe, Portugal and Brazil, absence of neonatal signs, a pituitary that may mimic a tumour and ACTH deficiency that appears up to the seventh decade. The early and midline genes (HESX1, LHX3, LHX4, OTX2, SOX2, SOX3, GLI2, ROBO1, CDON) are associated with EPP, PSIS and cervical, cerebellar, ocular or limb malformations, with incomplete penetrance, variable expressivity, parental mosaicism and an oligogenic component. The genes of other systems (FOXA2, NFKB2, EIF2S3, KCNQ1, RNPC3, PNPLA6, CCDC149) lead the endocrinologist to hyperinsulinism, immunodeficiency, epilepsy, gingival fibromatosis, ovarian insufficiency or retinal dystrophy.

Diagnosis rests on assessment of all axes, thin-section MRI and genetic testing with copy number analysis, bearing in mind that a negative test does not exclude a genetic cause, that the proportion of detectable variants in a gene is not equivalent to clinical sensitivity and that an isolated deficiency may become combined. In the newborn, stimulation tests are contraindicated, the random GH of the first week and the critical sample during hypoglycaemia are informative, and newborn screening based on TSH alone does not detect central hypothyroidism.

Treatment is replacement by axis, with three constant rules: glucocorticoid before levothyroxine, reassessment of cortisol and FT4 after starting GH and the lowest safe dose of hydrocortisone in the child. Levothyroxine is titrated by FT4 and not by TSH; hydrocortisone is used at about 8–10 mg/m²/day in the child, with sick-day rules and emergency doses by age or weight; daily or long-acting GH requires an individualised dose and, in the infant with multiple deficiencies on LAGH, hypoglycaemia monitoring; pubertal induction and fertility follow the hypogonadotropic hypogonadism consensus, with gonadotrophins and not clomifene. The sources diverge on levothyroxine in pregnancy, sick-day doses and the maintenance dose of hydrocortisone, and several paediatric doses of sex steroids are off-label in Portugal. There is no gene-directed treatment; transplantable pituitary organoids are at the preclinical stage. Follow-up is lifelong, includes transition without interruptions of GH and surveillance for new deficiencies, and counselling depends on the inheritance mechanism of each gene, with testing of younger siblings so that replacement can be started early.

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