Septo-Optic Dysplasia (De Morsier Syndrome)

Syndromic class within the hypothalamo-pituitary-optic nerve spectrum: optic nerve hypoplasia, midline brain defects and evolving hypothalamo-pituitary dysfunction, of mainly sporadic and multifactorial aetiology, with a monogenic minority (HESX1, SOX2, SOX3, OTX2, PROKR2, FGFR1, FGF8, TCF7L1, ARNT2 and others).

Literature and regulatory information updated: 26 October 2026.

0. Initial Reference Table

Sources for the entity table: Orphanet, GeneGuidance, GeneReviews SOX2, Oxford Desk Reference and founding articles [1, 9–15, 17–20, 26, 27, 36, 42, 43].

1. Introduction

1.1. Historical overview

The association between absence of the septum pellucidum and optic nerve anomalies was first described by Reeves in 1941, in a report published in the Bulletin of the Johns Hopkins Hospital [6]. In 1956, Georges de Morsier, in a study of craniocerebral dysraphias published in the Schweizer Archiv für Neurologie und Psychiatrie, designated agenesis of the septum pellucidum with malformation of the optic tract as «septo-optic dysplasia», and the eponym De Morsier syndrome spread from then on [5, 6]. According to Rush and Bajandas (1978), cited by OMIM, it was de Morsier who coined the term in 1956 [8]. In 1970, Hoyt and colleagues published in the Lancet the article «Septo-optic dysplasia and pituitary dwarfism», which added pituitary dysfunction, mainly growth hormone (GH) deficiency, to the picture and established the triad that still defines the entity today [5, 6]. In the following decades, reports broadened the spectrum: Brook and colleagues (1972), Haseman and colleagues (1978), with precocious puberty associated with SOD and hypothalamic hypopituitarism, Blethen and Weldon (1985), with SOD and hypopituitarism in first cousins, Morgan and colleagues (1985), who showed the overlap of syndromes with absent septum pellucidum, and Hanna and colleagues (1989), who studied puberty in these patients [5]. Harris and Haas (1972) described hypoplastic optic discs with a double contour, absent septum pellucidum and GH deficiency and found no Mendelian basis; Benner and colleagues (1990) described two siblings with SOD and corpus callosum and cerebellar anomalies suggestive of a Dandy-Walker variant, and Wales and Quarrell (1996) two siblings born to consanguineous parents, with hypoglycaemia in the first hours of life and undetectable GH, ACTH, LH and FSH, who would become the first patients with a HESX1 variant [8]. Lubinsky (1997) proposed that SOD was a vascular disruption sequence, a hypothesis that later epidemiological data reinforced [5–7].

The first monogenic basis was identified in 1998 by Dattani and colleagues, who described in Nature Genetics two siblings with SOD homozygous for a missense variant in the HESX1 homeodomain, with loss of deoxyribonucleic acid (DNA) binding, and a Hesx1−/− mouse model with a reduced forebrain, anophthalmia or microphthalmia, an olfactory defect, a bifurcated Rathke's pouch and anomalies of the corpus callosum, commissures and septum pellucidum [44]. These were followed by heterozygous HESX1 variants with incomplete penetrance (Thomas and colleagues, 2001), the first variant in the eh1 repressor domain in a Brazilian patient from São Paulo (Carvalho and colleagues, 2003), truncating SOX2 variants in anophthalmia (Fantes and colleagues, 2003), SOX3 dosage changes (Woods and colleagues, 2005), OTX2 variants in ocular malformation cohorts (Ragge and colleagues, 2005), those in FGF8 (McCabe and colleagues, 2011), PROKR2 and FGFR1 (Raivio and colleagues, 2012), ARNT2 (Webb and colleagues, 2013) and TCF7L1 (Gaston-Massuet and colleagues, 2016) [13, 27, 42, 43, 45–49]. Screening of 724 unrelated patients showed that HESX1 coding variants explain less than 1% of cases, and the largest published molecular cohort, with 1765 patients with or at risk of congenital hypopituitarism, identified variants in 10% [38, 50].

1.2. Nomenclature and reclassifications

The historical attribution has been contested. Garcia-Filion and Borchert argue that recognition of the association between ONH and hypopituitarism is due to William Hoyt and not to de Morsier, who never described a case of ONH nor recognised the association with hypopituitarism or with absent septum pellucidum; they therefore consider «septo-optic dysplasia» and «De Morsier syndrome» historically inaccurate and clinically misleading terms, and prefer «optic nerve hypoplasia syndrome», because hypopituitarism, developmental delay and autism are independent of septum pellucidum development [2, 51]. Polizzi and colleagues proposed the designation «SOD complex» in 2006 [6]. The Great Ormond Street Hospital (GOSH) group proposed «hypothalamo-pituitary-optic dysplasia» (HPOD) and the Manitoba group uses «septo-optic-pituitary dysplasia» [3, 4]. Orphanet adopts «septo-optic dysplasia spectrum» (ORPHA:3157) [1]. In 2022, an international working group renamed central diabetes insipidus as arginine vasopressin deficiency (AVP-D) and the nephrogenic form as arginine vasopressin resistance; this article uses the new designation, retaining «diabetes insipidus» when citing series that use it [52]. The term «SOD-plus» designates SOD with malformations of cortical development (schizencephaly, polymicrogyria, heterotopias) [53, 54].

1.3. Definition of the entities in scope

Classic SOD is a clinical diagnosis that requires at least two of the three elements: unilateral or bilateral ONH; pituitary hormone abnormalities; midline brain defects, including agenesis of the septum pellucidum and/or corpus callosum [5, 6, 36]. Isolated elements do not meet the criterion, although there is debate about the mild end of the spectrum [6]. The class includes sporadic SOD, which is the majority; monogenic SOD, with HESX1 (AR and AD), SOX2 (AD), SOX3 (X-linked), OTX2 (AD), PROKR2, FGFR1 and FGF8 (variable inheritance), TCF7L1 and ARNT2 (AR, Webb-Dattani syndrome); SOD-plus; and SOD with digital anomalies, described as a recurrent pattern syndrome by Harrison and colleagues in 2004 [1, 36, 55]. Isolated ONH (ORPHA:637061) and polymicrogyria with ONH (ORPHA:250972) are part of the spectrum [10, 11]. Combined pituitary hormone deficiency (CPHD) of genetic cause (POU1F1, PROP1, HESX1, LHX3, LHX4) is covered here only as regards the pituitary spectrum of SOD; congenital hypogonadotropic hypogonadism and Kallmann syndrome share PROKR2, FGFR1, FGF8 and ANOS1 [27, 28]. When SOD is part of a broader brain defect, such as holoprosencephaly, the main entity becomes that defect [5, 29].

2. Molecular Genetics and Pathophysiology

2.1. Embryology of the anterior forebrain, visual pathways and pituitary

The presumed pathogenesis of SOD is an early defect in the morphogenesis of the anterior midline structures. Smith locates it in a sagittal view of the brain of a 38-day embryo and outlines the cascade: incomplete morphogenesis of the anterior midline structures leads to a hypothalamic defect, optic chiasm hypoplasia explains the visual impairment and pendular nystagmus, and absence of the septum pellucidum results from the same disturbance [5]. Webb and Dattani place the anomaly at 4–6 weeks of gestation, in the morphogenesis of the anterior neural plate [6]. The commissures begin to form from 6 weeks; at 10 weeks the first fibres cross the lamina terminalis to form the anterior commissure; the corpus callosum appears from 11 weeks and its growth locally thins the lamina terminalis, which gives rise to the septum pellucidum; at 18–20 weeks the corpus callosum has its adult shape, although it continues to thicken and grow caudally for months [36].

The adenohypophysis (anterior and intermediate lobes) derives from Rathke's pouch, of oral ectodermal origin, and the neurohypophysis derives from the neural ectoderm of the ventral diencephalon. Five cell lineages produce six hormones (GH, thyroid-stimulating hormone or TSH, luteinising hormone or LH, follicle-stimulating hormone or FSH, corticotropin or ACTH, prolactin or PRL); arginine vasopressin (AVP) and oxytocin are produced in the supraoptic and paraventricular nuclei and transported along the stalk [33]. In the mouse, Hesx1 is detectable in the anterior forebrain from E7.5 to E8.5 and in Rathke's pouch from E8.5 to E13.5, declining from E12; its decrease allows activation of downstream genes such as Prop1, and its initial activation may depend on LHX1 and OTX2 [33]. Otx2 is expressed from E10.5 to E14.5 in the ventral diencephalon and from E10.5 to E12.5 in Rathke's pouch and regulates RX1, PAX6, SIX3, LHX2, MITF, GBX2 and HESX1 [33]. BMP4 is the first secreted molecule detected in the prospective infundibulum (E8.5) and is essential for formation of Rathke's pouch; FGF8 is expressed in the infundibulum from E9.5; GLI2, a mediator of the Sonic hedgehog (SHH) pathway in the ventral diencephalon, induces BMP4 and FGF8 [33]. In human pituitary development, SOX2 is expressed at 4.5–9 weeks in Rathke's pouch and persists in the adenohypophysis and diencephalon, as well as in sensory placodes, inner ear, lens, retina and optic nerve [33]. The common embryological origin of the visual pathways, hypothalamus and pituitary and the disruption of inductive signals explain the combination of ocular and pituitary phenotypes [53].

2.2. Aetiological architecture of the class

SOD is aetiologically heterogeneous and mainly sporadic [5, 36]. Teratogens (intrauterine viral infection, valproic acid, alcohol), vascular disruption and AR or AD variants in transcription factors of forebrain and pituitary development have been proposed [5]. Young maternal age, primiparity and first-trimester bleeding support the vascular disruption sequence hypothesis: in the West Midlands series, median maternal and paternal ages were 21 and 23.5 years, versus British means of 29.3 and 32.4 years (p<0.001), and first-trimester bleeding occurred in 12/48 (25%) versus 0.07% in the British population (p<0.001) [7]. In the prospective North American cohort of Children's Hospital Los Angeles (CHLA), with 204 patients up to 36 months, young maternal age and primiparity predominated, with frequent preterm labour, vaginal bleeding, low maternal weight gain and maternal weight loss, without confirmation of alcohol or drugs as factors [56]. A review of 50 years of epidemiology concluded that exposures to recreational drugs, medicines and viral infections are rare in large cohorts, that familial cases and gene variants are rare, and that prenatal nutrition, weight gain and deprivation may play a role [57]. In the Swedish registry, ONH was associated with young maternal age, first parity, maternal smoking, preterm birth and, suggestively, fertility drugs and antidepressants [58]; a 2026 narrative review considered the evidence on tobacco and ONH limited and confounded by prematurity and growth restriction, with no established causality [59]. The Manitoba neuropathological study, with 21 autopsies, attributed 12 cases to intrauterine or perinatal vascular lesions, 3 to genetic causes (1 with holoprosencephaly), 2 to intrauterine infection and 1 to an arachnoid cyst with hydrocephalus, and concluded that SOD is a clinical syndrome and not a single neuropathological entity [60].

The monogenic fraction is small. In the GOSH cohort of 1765 patients with or at risk of congenital hypopituitarism, variants were identified in 178 (10%), distributed among GH1/GHRHR (51/414 tested), PROP1 (17/253), POU1F1 (15/139), SOX2 (13/59), GLI2 (7/106), LHX3/LHX4 (8/110), HESX1 (8/724), SOX3 (9/354), OTX2 (5/59), SHH (2/64) and TCF7L1, ANOS1, FGFR1 and FGF8 (2/585 each) [38]. In SOD in the GOSH longitudinal cohort, genetic testing in 144 of 171 patients identified variants in 6 (4.2%): PROKR2 in 5 and SOX2 in 1 [3]. Genome sequencing in 29 Swedish patients with ONH had a pathogenic or likely pathogenic yield of 4/29 (14%), mainly in non-isolated ONH, with variants in KIF7, COL4A1, COL4A2 and a 341 kb deletion of SOX5 [61]. Trio exome sequencing of 34 CHLA patients with ONH showed no monogenic causality and pointed to a polygenic architecture, with 161 candidate genes enriched in neurodevelopmental ontologies, expressed in retinal ganglion cells and overlapping with autism genes [62]. A 2026 review in Endocrine Reviews stresses the overlap of genes between congenital hypopituitarism, SOD and holoprosencephaly and the influence of genetic background and environment, with animal models of gene-environment synergy [63].

2.3. Class table: genes, entities and distinctive features

2.4. HESX1

HESX1 encodes a transcriptional repressor with a paired-like homeodomain, expressed early in the prospective forebrain and later restricted to Rathke's pouch. It binds a palindromic site, heterodimerises with PROP1 and antagonises PROP1-mediated activation, repressing through recruitment of the Groucho/TLE1 corepressors [9]. Patients show three distinct molecular defects: abolished DNA binding (homozygous p.Arg160Cys, historically Arg53Cys from its position in the homeodomain; heterozygous p.Arg109Gln), markedly reduced binding (p.Ser170Leu) and defective TLE1 recruitment with intact binding and partial loss of repression (p.Ile26Thr in the eh1 domain) [9, 44–46, 66]. The consequence is adenohypophyseal hypoplasia with variable deficiencies, a thin or interrupted stalk and an ectopic posterior pituitary on MRI, with or without ONH and midline forebrain defects [9]. By 2010, 5 homozygous variants had been described, with recessive inheritance and complete penetrance, and 8 heterozygous ones, with dominant inheritance, variable penetrance and a milder phenotype [6]. Thomas and colleagues, screening 228 patients with congenital pituitary defects, found three heterozygous variants in patients with mild pituitary hypoplasia or SOD, with a variable phenotype in heterozygous family members, and Hesx1+/− mice showed a mild SOD phenocopy in a small proportion [45]. McNay and colleagues re-evaluated 724 unrelated patients (314 with SOD) and 126 patients from 66 families with familial hypopituitarism and found an overall incidence of coding variants below 1%, as well as a new variant p.Glu149Lys in a patient with isolated GH deficiency and digital anomalies [50]. The HESX1 phenotype is not limited to classic SOD: the homozygous p.Ile26Thr patient from São Paulo had evolving CPHD, a thin stalk, adenohypophyseal hypoplasia and an ectopic posterior pituitary without midline or optic nerve anomalies, and the Japanese child with heterozygous p.Arg109Gln presented with neonatal hypoglycaemia due to central adrenal insufficiency, central hypothyroidism and GH deficiency, without features of SOD [46, 66]. The human gene was cloned by Dattani and colleagues in 1998: it encodes a 185-amino-acid protein, has 4 coding exons and was then mapped by fluorescence in situ hybridisation to 3p21.2-p21.1, which is the location reproduced by Smith; the current location is 3p14.3 (GRCh38 coordinates 3:57,197,838–57,227,615) [5, 21, 22]. Brickman and colleagues (2001) defined a minimal repressor domain of 36 amino acids, able to suppress the activity of homeodomain activators [22]. OMIM entry 182230 groups three allelic HESX1 phenotypes, all with AD and AR inheritance: SOD, CPHD 5 (without ONH or midline defects) and GH deficiency with pituitary anomalies [8]. In the family described by Wales and Quarrell (1996), in which Dattani identified the homozygous p.(Arg160Cys) variant in the two siblings with the complete syndrome, the variant was heterozygous in 9 unaffected relatives, including both parents; the Arg160 residue is one of the most conserved in homeodomains and contacts the DNA phosphate backbone [22]. Cohen and colleagues (2003) described an inverse mechanism, in a heterozygous frameshift variant that increased DNA binding and repression of PROP1-dependent activity, and Sobrier and colleagues (2006) described in two homozygous Italian patients a life-threatening neonatal phenotype (hypoglycaemic seizures, respiratory distress and shock, with neonatal death in the family of one of them), adenohypophyseal aplasia in a flat sella turcica, a normally placed posterior pituitary and normal optic nerves [8, 22]. The patient with p.(Glu149Lys) had supernumerary digits, and his son, mother and a brother were apparently unaffected carriers; the variant lost the ability to repress PROP1-mediated activation [22].

The following table normalises the published HESX1 variants with a pituitary phenotype. Historical nomenclature was converted in VariantValidator (MANE Select transcript NM_003865.3, GRCh38) and the classification is that of ClinVar consulted in October 2026 [6, 21, 67].

The conversion of «Arg53Cys» to p.(Arg160Cys) results from the original publication numbering the residue within the homeodomain; the Tajima variant was described as an insertion «306/307insAG» and is normalised as the duplication c.305_306dup, because HGVS requires insertions that repeat the adjacent sequence to be described as duplications at the most 3′ position [21, 68]. The Sobrier and Cohen variants were normalised in VariantValidator from the OMIM notations and the ClinVar records corresponding to the OMIM alleles (601802.0007 and 601802.0006); the historical genomic notation «g.1684delG» corresponds to NM_003865.3:c.525del [21, 22, 67]. The variants K176T and the Alu insertion in exon 3, from the Webb and Dattani table, are not listed as OMIM alleles and were not normalised [6]. The high number of heterozygous variants with conflicting or uncertain significance classification reflects incomplete penetrance and the difficulty of attributing causality to dominant HESX1 alleles [45, 67].

2.5. SOX2

SOX2 is a single-exon gene encoding a 317-amino-acid protein with an HMG (high mobility group) DNA-binding domain (amino acids 40–111), a partner-binding region and a C-terminal transactivation region; the N-terminus has short polyglycine and polyalanine repeats [26]. It is part of activating complexes for ocular development genes (PAX6, MAF1) and is an early marker of neurulation, expressed in the developing nervous system, the genital ridge and the foregut [26]. The mechanism is heterozygous loss of function through haploinsufficiency (ClinGen score 3); because it is a single-exon gene, there are no alternative transcripts or nonsense-mediated decay, and loss-of-function variants are distributed across the whole exon [12, 26]. Penetrance of non-mosaic loss-of-function variants is complete and all individuals with normal eyes have extraocular defects [26]. About 2–3% of affected individuals, and about 20% of those with bilateral anophthalmia or severe microphthalmia, have 3q26.33 deletions that include SOX2, from 1.5 to about 9 Mb, without marked phenotypic difference according to size, including unbalanced translocations and apparently balanced translocations with a deletion at the breakpoint; duplications including SOX2 (40 kb to 104 Mb) do not cause structural eye defects but are associated with developmental delay, intellectual disability, hypotonia and gastro-oesophageal reflux [26]. The term «AEG» (anophthalmia, oesophageal atresia and genital anomalies) does not designate a distinct disease but part of SOX2 disorder, and the umbrella term MAC (microphthalmia-anophthalmia-coloboma) is inappropriate because coloboma is not frequent [26].

The notations and their correspondence were confirmed in VariantValidator and ClinVar; the form «c.70_89del20» is discouraged by current HGVS, which does not state the number of deleted nucleotides [6, 21, 26, 67]. OMIM individualises a second SOX2 phenotype, «ONH and central nervous system anomalies» (206900), defined by the two missense variants of Kelberman and colleagues (2006): in a screen of 235 probands with congenital hypothalamo-pituitary disorders, 6 patients with anophthalmia or microphthalmia had de novo variants and 2 patients with bilateral ONH, without anophthalmia, had variants inherited from phenotypically normal parents; all had associated anomalies, such as adenohypophyseal hypoplasia, hypogonadotropic hypogonadism, defects of the corpus callosum and mesial temporal structures, hypothalamic hamartoma, learning difficulties, sensorineural deafness or oesophageal atresia [23]. These two variants now have a conflicting classification in ClinVar, consistent with transmission from unaffected parents [23, 67]. The Sox2+/− mouse has no eye defects but has abnormal adenohypophyseal development, with reduced GH, LH and TSH and decreased male fertility [23]. Non-progressive early-onset pituitary tumours associated with SOX2 haploinsufficiency (Alatzoglou 2011) and a mother with idiopathic hypogonadotropic hypogonadism, normal eyes and probable mosaicism, with two children with microphthalmia (Stark 2011), have also been described [23].

2.6. SOX3

SOX3 is a single-exon HMG factor, one of the first expressed in the central nervous system and required for hypothalamo-pituitary development, including the infundibulum [14]. It is dosage-sensitive: loss of function, polyalanine tract changes and duplications cause X-linked hypopituitarism [14, 48]. An 11-alanine expansion is associated with GH deficiency with variable learning difficulties (Laumonnier 2002); a 7-alanine expansion, described by Woods and colleagues in a family with three brothers, caused panhypopituitarism with an absent infundibulum, severe adenohypophyseal hypoplasia and an ectopic posterior pituitary, with reduced transcriptional activity and defective nuclear localisation of the protein [14, 48]. The same series described the smallest Xq27.1 duplication then known (685.6 kb, including SOX3) in two brothers with variable hypopituitarism, callosal anomalies and an absent infundibulum; duplications of only 321 kb were later described (Arya 2019) [14, 48]. In HGVS, the 33 bp duplication (11 alanines) described by Laumonnier corresponds to NM_005634.3:c.712_744dup p.(Ala238_Ala248dup) (ClinVar 9868, likely pathogenic) and the 21 bp duplication (7 alanines) described by Woods corresponds to NM_005634.3:c.711_731dup p.(Ala242_Ala248dup) (ClinVar 9870, pathogenic); the original descriptions (711-743dup; Ala(7)240ins241) were shifted to the 3′ position required by HGVS [21, 24, 67]. The Woods abstract describes three affected brothers with the 7-alanine expansion, and OMIM describes four brothers born to consanguineous parents from Qatar, with a heterozygous mother without skewed X inactivation in blood [24, 48]. Solomon and colleagues (2004) found SOX3 duplications in all 5 families with X-linked hypopituitarism and Xq duplications studied, but in 2007 did not replicate the duplication in 3 of these families without intellectual disability, confirming it only in the families with intellectual disability [24]. In the mouse, Sox3 is expressed in the infundibulum and presumptive hypothalamus and its deletion causes defects of pituitary function and midline structures, with altered properties of ventral diencephalic cells and secondary abnormal development of Rathke's pouch, which does not express the gene [24]. ClinGen gene-disease validity is moderate for X-linked pituitary hormone deficiency with or without intellectual disability (June 2026), with a haploinsufficiency score of 0 and a triplosensitivity score of 2 [14]. Female carriers are generally unaffected or mildly affected, and several boys inherited duplications from unaffected mothers (De Dominicis 2026) [14]. SOX3 regulatory rearrangements also cause position-effect disorders: SRY-negative 46,XX testicular disorder of sex development, X-linked congenital generalised hypertrichosis, neural tube defects and X-linked hypoparathyroidism [14]. SOX3 deletion has been described with persistent craniopharyngeal canal [33].

2.7. OTX2

OTX2 encodes a homeodomain transcription factor of the bicoid subfamily that binds the sequence TCTAATCCC and transactivates HESX1, POU1F1 and the IRBP gene; frameshift alleles abolish transactivation of the HESX1, POU1F1, GNRH1 and IRBP promoters, whereas C-terminal nonsense codons retain about half of the activity, without a dominant-negative effect; the ClinGen haploinsufficiency score is 3 [13]. The eye-brain-pituitary phenotype is dominant and highly variable, from bilateral anophthalmia to early-onset retinal dystrophy with normal globes; OTX2 is one of four genes for dominant non-syndromic Leber congenital amaurosis and severe early-onset retinal dystrophy, accounting for less than 1% of that group [13]. Pituitary involvement is independent of ocular severity, from isolated GH deficiency with a structurally abnormal pituitary to complete CPHD with neonatal hypoglycaemia; in a series of 5 patients, 2 had apparently normal pituitary function, with no genotype-phenotype correlation (Dateki 2010) [13]. Patients with an OTX2 variant without ocular involvement are rare: Diaczok and colleagues (2008), studying 8 pituitary transcription factor genes in 19 patients with hypopituitarism, identified heterozygous p.(Asn233Ser) (NM_021728.4:c.698A>G) in 2 patients with CPHD 6 (OMIM 613986), with a dominant-negative effect on the proximal HESX1 promoter in cellular studies; the variant is classified as of uncertain significance in ClinVar [21, 25, 33, 67]. The dominant-negative effect of this missense variant contrasts with the absence of a dominant-negative effect of truncating alleles [13, 25]. OMIM also describes a de novo nonsense variant in a 7-year-old boy with severe childhood-onset retinal dystrophy, night blindness and GH deficiency (Henderson 2009; S138X), which in the MANE transcript corresponds to NM_021728.4:c.437C>G p.(Ser146Ter) (ClinVar 30025), and a de novo 2 bp insertion in a 6-year-old Japanese boy with bilateral anophthalmia, short stature and CPHD (Tajima 2009; 576insCT), recorded in ClinVar as c.428_429dup p.(Ser144LeufsTer43) (ClinVar 30024); the numbering difference results from the authors numbering the short 289-amino-acid isoform or including the 2 non-coding exons, whereas the MANE transcript encodes the 297-amino-acid isoform [21, 25, 67]. The short isoform is the main product in the pituitary, thalamus and hypothalamus (Dateki 2010) [25]. Penetrance is reduced and parental gonosomal mosaicism has been documented repeatedly [13]. The somatic oncogenic role of OTX2 (amplification in medulloblastoma) does not imply a risk of medulloblastoma for carriers of germline variants [13].

2.8. PROKR2, FGFR1 and FGF8: the overlap with Kallmann syndrome

PROKR2 encodes a G protein-coupled receptor involved in neuronal migration and angiogenesis; it is associated with congenital hypogonadotropic hypogonadism, Kallmann syndrome and hypopituitarism of variable penetrance, including SOD and stalk interruption [33, 64]. Raivio and colleagues screened FGFR1, FGF8, PROKR2, PROK2 and KAL1 in 103 patients (35 with CPHD and 68 with SOD): three patients with SOD had heterozygous FGFR1 variants (p.S450F and p.P483S, with altered signalling, and c.336C>T p.T112T, predicted to affect splicing), one had a synonymous FGF8 variant (c.216G>A p.T72T) with an effect on splicing and signalling, and four patients with CPHD or SOD had PROKR2 loss-of-function variants (p.R85G, p.R85H, p.R268C); overall, FGFR1, FGF8 and PROKR2 were altered in 7.8% of patients [27]. The current ClinVar classification of these PROKR2 variants is conflicting for those at Arg85 (NM_144773.4:c.253C>G p.(Arg85Gly) and c.254G>A p.(Arg85His)) and benign or likely benign for c.802C>T p.(Arg268Cys), which illustrates the oligogenicity and incomplete penetrance of this group; the FGFR1 variants were not normalised [21, 67]. The Orphanet submission to GenCC linking PROKR2 to SOD has only the «supportive» level [17]. McCabe and colleagues studied FGF8 in 374 patients with SOD and 47 with holoprosencephaly or clefts: homozygous p.R189H in a girl born to consanguineous parents with semilobar holoprosencephaly, AVP-D and TSH and ACTH deficiencies, and heterozygous p.Q216E in a girl with corpus callosum agenesis, ONH and Moebius syndrome; FGF8 is expressed in the ventral diencephalon and the anterior commissural plate, and hypomorphic mice have fewer vasopressin and oxytocin neurons [49]. FGFR1 also causes Hartsfield syndrome (holoprosencephaly with ectrodactyly, absent septum pellucidum, corpus callosum agenesis, AVP-D and hypogonadotropic hypogonadism) [18].

2.9. TCF7L1 and ARNT2

TCF7L1, a repressor of the WNT/β-catenin pathway, is required in the prospective hypothalamus for the inductive signals of Rathke's pouch, and its function depends only on its repressor activity; two independent human missense variants (p.R92P and p.R400Q) were found in patients with forebrain and/or pituitary defects, with reduced repressor activity in vitro and in vivo [42]. ARNT2 encodes a bHLH-PAS factor, an obligate dimerisation partner, required for the hypothalamo-pituitary axis, postnatal brain growth and visual and renal function [15]. In the consanguineous family described by Webb and colleagues, the homozygous variant published as c.1373_1374dupTC eliminated the transcript and protein in fibroblasts through nonsense-mediated decay; the published notation is rejected by VariantValidator because the reference sequence is «CG» and not «TC», and the normalised form NM_014862.4:c.1372_1373dup p.(Tyr459ArgfsTer52) (ClinVar 805850, pathogenic) reproduces the published protein consequence [21, 43, 67]. ARNT2 is expressed in the developing central nervous system, including the hypothalamus, and in the embryonic renal tract [43].

The 2026 review by the Great Ormond Street Hospital (GOSH) group estimates that fewer than 5% of patients with SOD have a genetic diagnosis and adds per-gene data and other genes of the oculo-pituitary syndromes [53]. HESX1 variants explain less than 1% of SOD and hypopituitarism; about 30% of carriers have the complete triad, with anophthalmia, microphthalmia, ONH or optic nerve aplasia, GH deficiency is the most frequent, AVP-D has not yet been described, and 1.4% of 217 patients with Kallmann syndrome had a HESX1 variant with a normal pituitary on imaging [53]. In a cohort of 18 patients with SOX2 variants, 6 (33%) had short stature or GH deficiency and 8 (44%) genital anomalies or hypogonadotropic hypogonadism [53]. In OTX2 variants, pituitary deficiencies occur in about 30%, mainly of GH, and microphthalmia or anophthalmia in 2–3%, with retinal dystrophies, coloboma and ONH [53]. Other genes combine ocular and pituitary phenotypes: RAX (about 3% of anophthalmias and microphthalmias; a truncating homozygote with anophthalmia, panhypopituitarism with AVP-D, cleft lip and palate and absent pituitary), PAX6 (four cases of hypopituitarism described), BMP4 (anterior segment dysgenesis, pathological myopia in truncating variants, pituitary and brain malformations), ROBO1 (from isolated GH deficiency to stalk interruption, with ONH, microphthalmia, strabismus and ptosis; the most frequent gene in a large Argentinian congenital hypopituitarism cohort), TBC1D32 (ciliopathy with multiple pituitary deficiency, absent adenohypophysis and ectopic posterior pituitary; in one patient, chiasmal hypoplasia and polydactyly), MAGEL2 (Schaaf-Yang syndrome with GH, ACTH and AVP deficiencies and ONH), FOXA2 (hypopituitarism with congenital hyperinsulinism, choroidal coloboma and malformations of endodermal organs) and GLI2 (Culler-Jones syndrome: among 112 carriers, holoprosencephaly in only three; with truncating alleles, 62% had pituitary anomalies and polydactyly) [53].

2.10. Endocrine pathophysiology and correlations

The hypopituitarism of SOD is of hypothalamic origin, which explains the frequency of hyperprolactinaemia, the temporal evolution of the deficiencies and the possibility of precocious puberty coexisting with deficiency of other hormones [2, 3, 5]. In the CHLA cohort, initial prolactin before 36 months was raised in 72% of 125 patients; hyperprolactinaemia was associated with hypopituitarism (odds ratio, OR, 2.58; 95% confidence interval, 95% CI, 1.16–5.73) and specifically with GH deficiency (OR 2.77; 95% CI 1.21–6.34), but is not a reliable prognostic marker [69]. The GOSH comparison between SOD and multiple pituitary hormone deficiency without ONH (MPHD) showed that, in SOD with hypopituitarism (SOD+), deficiencies are less frequent and later than in MPHD, with hazard ratios (HR, SOD+ vs. MPHD) of 0.63 (0.45–0.89) for GH, 0.48 (0.34–0.69) for TSH, 0.55 (0.38–0.80) for ACTH and 0.28 (0.11–0.68) for gonadotropins, except AVP-D (HR 2.27; 0.88–5.9) [3]. Stalk and posterior pituitary anomalies were associated with more severe endocrine phenotypes and earlier deficiencies; an absent posterior pituitary was associated with early onset of all deficiencies except gonadotropin deficiency, whereas an ectopic posterior pituitary and pituitary stalk interruption syndrome (PSIS) were associated with all anterior deficiencies but were protective for AVP-D [3]. Laterality of ONH and midline anomalies had no clear association with time to deficiencies [3]. At CHLA, hypopituitarism, hypothalamic dysfunction, developmental delay and autism were independent of septum pellucidum development, and brain MRI did not predict hypopituitarism [2, 70]. Penetrance and expressivity are variable in almost all genes in the class: complete in recessive HESX1 forms and in SOX2 loss-of-function variants, incomplete in dominant HESX1 alleles, in OTX2, in SOX3 female carriers and in PROKR2/FGFR1 variants [6, 13, 14, 26, 27].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Frequency of the triad elements in cohorts

The frequency of each element depends on the entry criterion and the type of centre. In the West Midlands regional series (Birmingham Children's Hospital, 1998–2009), 227 patients had at least one element of the triad (55 with midline defects, 149 with ONH and 132 with hypopituitarism); 88 children met the definition of SOD (two of three elements; 52% boys), 21 (24%) had all three elements, 61% had anterior pituitary deficiency and 21.5% had AVP-D [7]. In the GOSH tertiary and quaternary cohort (171 patients with SOD diagnosed between 1994 and 2015), 64.9% had all three criteria, ONH was present in 89.9% (87.4% bilateral and 12.6% unilateral) and only 39/171 (22.8%) retained preserved pituitary function up to 14.12 years of follow-up (median 6.25 years) [3]. At the paediatric endocrinology centre in Michigan (USA; 80 patients, 2012–2014), ONH was present on MRI in 96%, hypothalamo-pituitary dysfunction in 55%, and 86% of these deficiencies were diagnosed by 2 years; dysfunction occurred in 51% when ONH was present, with (36%) or without (15%) septal or corpus callosum dysgenesis, and in 4% with isolated dysgenesis [71]. The review by Webb and Dattani, citing Morishima and Aranoff (1986), reports about 30% with complete manifestations, 62% with hypopituitarism and 60% with absent septum pellucidum [6]. Smith gives absence of the septum pellucidum in about 50% of cases, and Oxford Desk Reference cites an unidentified series with GH deficiency in 80%, ACTH deficiency in 60%, LH/FSH deficiency in 40% and diabetes insipidus in 35%, without denominator or period [5, 36]. McNay and colleagues, in 210 patients with SOD and detailed clinical information, found the complete triad in 60 (29%) and two elements in 150 (71%): ONH with a midline defect in 38 (18%), ONH with hypopituitarism in 83 (39%) and hypopituitarism with a midline defect in 29 (14%) [8]. In 55 patients with ONH studied by Birkebaek and colleagues (2003), 49% had an abnormal septum pellucidum on MRI, 64% an abnormality of the hypothalamo-pituitary axis on MRI and 49% endocrine dysfunction, more frequent with an abnormal septum (56% versus 39%) [8]. Willnow and colleagues (1996), in 18 German patients, described severe psychomotor delay in 14 and short stature in all, with GH deficiency and absent response to thyrotropin-releasing hormone (TRH) as the most common abnormalities [8]. In national surveillance by the Australian Paediatric Surveillance Unit (APSU, 2023–2024), of the 12 cases notified, 7 were diagnosed in the neonatal period, 8 had hormone deficiencies (4 with multiple deficiency), 7/12 had a septum pellucidum anomaly, 2/12 a corpus callosum anomaly and 5/12 no midline defect [32].

3.2. Ophthalmological manifestations

The optic nerve, chiasm and infundibulum are hypoplastic, with pendular nystagmus, visual impairment and sometimes field defects [5]. ONH is a non-progressive congenital anomaly, unilateral or bilateral, total or partial; the optic disc is small and pale, sometimes surrounded by a peripapillary ring of pigmentation («double-ring sign»); presentation is usually with nystagmus in bilateral cases and strabismus in unilateral cases, and visual function ranges from near normal to complete loss, difficult to predict in infancy [65, 72]. Smith reproduces a fundus photograph of a 4-year-old child with SOD, reduced vision, pendular nystagmus and growth failure due to GH deficiency, with hypoplastic optic nerve heads and an aberrant vascular arrangement [5]. In Michigan, diagnosis was prompted by nystagmus in 36% and by strabismus in 13.8% [71]. In Olmsted County, among 19 children with ONH, 84% had bilateral disease, 47% reduced acuity, 42% strabismus and 26% nystagmus [31]. Webb and Dattani report significant visual impairment in 23% [6]. On optical coherence tomography (OCT) of 37 eyes with ONH in Stockholm, the peripapillary nerve fibre layer and the ganglion cell complex were thinner than in 140 controls (p<0.001); best corrected visual acuity correlated with Bruch's membrane opening (r=0.71), which explained 48% of the variance, and ganglion cell complex thinning corresponded to the presence and location of field defects [73]. OTX2 may be associated with early-onset retinal dystrophy with normal globes, and SOX2 disorder with anophthalmia or microphthalmia (section 3.7) [13, 26].

3.3. Endocrine manifestations

GH deficiency is the most common; it is followed, in variable order depending on the series, by central hypothyroidism, secondary or tertiary adrenal insufficiency, gonadotropin deficiency and AVP-D [3, 6, 71]. In a single-centre series of 197 patients with ONH, AVP-D appeared earliest (median 0.6 years; 0–12.9), followed by hypothyroidism (1.3 years; 0–15.4), GH deficiency (2.8 years; 0–16.8), ACTH deficiency (3.2 years; 0–15.4), precocious puberty (7.3 years; 6.6–8.1) and hypogonadotropic hypogonadism (13.7 years; 13.2–14.8); hypothyroidism was the most frequent deficiency, and visual loss and nystagmus the most common ophthalmological findings [53]. At GOSH, the median age at first deficiency in SOD+ was 1.78 years (CI 1.2–2.5), versus 0.18 years in MPHD, and 90% of SOD+ patients had their first deficiency by 8.54 years (MPHD: 4.80 years); each additional deficiency increased the risk of an early deficiency (HR 1.59; 1.36–1.85) [3]. Up to 70 patterns of evolution from 16 combinations were observed; the most frequent combination was GH+TSH+ACTH (30.7% in SOD+; 49.0% in MPHD); isolated deficiencies in SOD+ were of GH in 21.6%, TSH in 3.6%, ACTH in 1.8% and gonadotropins in 0.9%, and AVP-D was never isolated [3]. GH deficiency was absent in 11 SOD+ patients (8.3%), ten of whom were over 1 year old at diagnosis of the first deficiency; 5 patients had GH neurosecretory dysfunction between 2.55 and 14.64 years, all with a small adenohypophysis; and 10/78 (13.8%) SOD+ patients with TSH deficiency had mildly raised TSH (above 6 mU/L, up to 9.8 mU/L) after exclusion of primary hypothyroidism [3]. AVP-D was diagnosed before 4 years in all 5 patients with MPHD, but 8/29 (27.6%) SOD+ patients had a late diagnosis, between 7.13 and 16.8 years [3]. In Stockholm, among 65 patients with ONH under 20 years, 29% had pituitary deficiency and 19% multiple deficiency, in both unilateral and bilateral ONH [74]. At CHLA, 69% of 146 children with ONH diagnosed before 24 months had hypopituitarism at 5 years [70].

Puberty ranges from delayed to precocious. At GOSH, spontaneous puberty at the expected age (8–12 years in girls, 9–13 years in boys) occurred in 54/66 (81.8%) patients with SOD, 7/15 (46.7%) with MPHD and 13/14 (92.8%) with ONH; probable gonadotropin-releasing hormone (GnRH) deficiency was 15.8% in SOD and 37.5% in MPHD; 9.5% of patients with SOD were treated for delayed or slow puberty and 7.0% for precocious or rapidly progressive puberty (4 with central precocious puberty), almost all with a small adenohypophysis [3]. At minipuberty, 41/96 (42.7%) boys with SOD had undervirilised genitalia (isolated micropenis 7.3%, isolated hypospadias 3.1%, isolated cryptorchidism 13.5%, two elements 16.7%, three elements 2.1%), versus 70.0% in MPHD; in the undervirilised boys tested, peak LH after GnRH was 5.35 international units (IU)/L in SOD and 0.10 IU/L in MPHD, and testosterone after 3 days of human chorionic gonadotropin (hCG) was 9.74 versus 2.67 nmol/L [3]. Haseman and colleagues had described sexual precocity in SOD in 1978, and Smith lists occasional hypersecretion of GH, ACTH and PRL [5].

Obesity is frequent: at the last GOSH visit, 51/161 (31.1%) patients with SOD were obese, 3 with extreme obesity (body mass index, BMI, above 4 standard deviations, SD), versus 41.2% in MPHD and 12.1% in ONH; obesity was more frequent with AVP-D (56.3% versus 29.4%; p=0.003), and 5.6% of patients with SOD were underweight [3]. At CHLA, 31% had a BMI at or above the 85th centile at 5 years [69]. In a GOSH case-control study in children aged 2–19 years, hyperphagia measured by the Dykens scale was the same in hypothalamic obesity (congenital SOD or suprasellar tumour) and common obesity, with similar hormone profiles (high insulin and leptin, low ghrelin and agouti-related protein, AgRP); the rate of BMI increase was associated with lower alpha-melanocyte-stimulating hormone (αMSH) [75].

3.4. Neurological and neurodevelopmental manifestations

In Barkovich's MRI series, SOD was divided into two patterns: one with schizencephaly, septal remnants and a tendency to seizures or visual impairment, attributable to a disruptive event in the first trimester, and another without schizencephaly, with diffuse white matter hypoplasia (including the optic radiations), ventriculomegaly, complete absence of the septum and more marked hypothalamo-pituitary dysfunction, close to midline prosencephalic dysgenesis [53]. In a multicentre cohort with systematic MRI phenotyping, Riedl and colleagues frequently found malformations of cortical development, hypoplasia of the corpus callosum and anomalies of the hippocampus and rostral falx; hippocampal and falx anomalies were associated with neurological symptoms and developmental delay, which supports SOD-plus as an extended phenotype of the same spectrum rather than a separate entity [53]. A systematic review cited in the same review estimates that up to 35% of children in the SOD spectrum have clinically relevant ASD symptoms [53].

Central nervous system findings include agenesis or hypoplasia of the corpus callosum, microcephaly, schizencephaly, polymicrogyria, grey matter heterotopia, fusion of the anterior fornices and arachnoid cysts; occasionally cortical atrophy, lissencephaly, hydrocephalus, aqueductal stenosis and vascular disruptive defects [5]. Seizures in SOD are frequently secondary to hypoglycaemia due to GH and/or cortisol deficiency rather than to a primary brain anomaly [36]. In a North American series of 107 children with SOD (2013–2023), seizures occurred in 52/103 (50.5%), with a median age at onset of 9 months; 82.6% of patients with seizures had an abnormal neurological examination, and seizures were associated with global delay (present in 43.0%), autism spectrum disorder (ASD), ventriculomegaly and schizencephaly, but not with the combinations of diagnostic criteria [35]. In the prospective CHLA cohort, 71% of 73 children with ONH had developmental delay at 5 years (39% in unilateral and 78% in bilateral ONH); corpus callosum hypoplasia and hypothyroidism were associated with a worse outcome, absent septum pellucidum was not, and 4 of 6 patients without a neuroradiological or endocrine anomaly had delay [76]. In Stockholm, mean full-scale intelligence quotient was 84.4 in bilateral ONH and 99.4 in unilateral ONH (p=0.049), with intellectual disability in 56% and 9%, respectively, and ASD in 17%; neurological deficits occurred in 47%, cerebral palsy in 9% and epilepsy in 14% [74, 77]. In the GOSH developmental vision service, among 83 children with ONH or SOD and profound or severe visual impairment, 58% had at least one difficulty with social interaction, communication or repetitive behaviours and 31% had clinical ASD (36% in SOD and 26% in ONH), diagnosed mainly between 2 years 4 months and 4 years 6 months [34]. In the Manitoba population-based study (124 patients diagnosed between 1990 and 2019 versus 620 controls), comorbidities were developmental delay or intellectual disability (OR 6.9; 3.3–14.4), ASD (OR 4.0; 2.0–8.3), epilepsy (OR 14.9; 6.1–36.5) and cerebral palsy (OR 40.9; 14.0–119.6) [4]. Smith estimates intellectual disability in 30% of cases, mainly with associated central nervous system defects, and a good intellectual prognosis in a child with absent septum pellucidum and ONH without other defects [5]. According to Oxford Desk Reference, about half of cases have moderate or severe developmental delay [36]. Other occasional neurological associations are hemiplegia, spasticity, athetosis and cranial nerve palsy [5].

3.5. Sleep, thermoregulation, appetite and smell

Hypothalamic dysfunction also manifests as sleep-wake rhythm disturbance, thermal instability and excessive appetite [6]. In six children with SOD studied at GOSH with 2-week actigraphy and 24-hour hourly serum melatonin, two produced virtually no melatonin and had fragmented sleep, one had a normal profile with an arrhythmic pattern and three had fragmented sleep; none had non-24-hour disorder or phase delay [78]. Altered thermoregulation was a common feature of the five children with sudden death described by Brodsky and colleagues [79]. Anosmia is among the associations to be sought in the history [6]. In a quantitative MRI study of 37 patients in the SOD spectrum, olfactory sulcus depth and length and bulb width, normalised to the biparietal diameter, were associated with consensus olfactory anomaly scores, with moderate reproducibility [80].

3.6. Neonatal presentation

Birth weight and length are usually normal; the warning signs are hypoglycaemia and micropenis [33]. The table summarises the correspondence between neonatal signs and deficiencies [33].

In ACTH deficiency, cholestasis appears in the first 2 weeks, transaminases rise after 2–4 weeks with normal gamma-glutamyl transferase and cholestasis resolves about 10 weeks after hydrocortisone; micropenis is defined as a stretched penile length below −2.5 SD (below 1.5 cm at 30 weeks, 2 cm at 34 weeks and 2.5 cm at term); in TSH deficiency there is prolonged jaundice, drowsiness, thermal dysregulation, umbilical hernia, dry skin, bradycardia, macroglossia and constipation; neonatal AVP-D manifests as polyhydramnios, polyuria, weight loss, irritability, dehydration and hypernatraemia [33]. Smith adds jaundice, apnoea, hypotonia and seizures in newborns, and neonatal intrahepatic cholestasis among the occasional anomalies [5].

3.7. Gene-specific phenotypes

SOX2 disorder had been described in 174 individuals from 157 families by 2020: 44% had bilateral anophthalmia, 13% anophthalmia with contralateral microphthalmia and 12% bilateral microphthalmia, and the remainder had a spectrum including coloboma, ONH or optic nerve aplasia, cataract, retinal dysplasia and anterior segment dysgenesis; 13 individuals with loss-of-function variants had structurally normal eyes [26]. On MRI, malformation or heterotopia of the mesial temporal structures, pituitary hypoplasia and agenesis or dysgenesis of the corpus callosum are core findings; septum pellucidum defects, cerebellar hypoplasia, hypothalamic hamartoma, arachnoid cyst and sellar or suprasellar tumours have been observed in several individuals [26]. Most have some pituitary axis dysfunction when GH and gonadotropins are measured in detail; hypogonadotropic hypogonadism has been described in 20 individuals, including two women with normal eyes; in boys, micropenis and cryptorchidism are frequent; in girls, a hypoplastic uterus, ovarian or vaginal agenesis and vaginal adhesions may occur [26]. Dystonia may progress to status dystonicus, an emergency triggered by major physiological stress; spasticity occurred in 13 individuals, seizures in 22, moderate non-progressive sensorineural deafness in 7 and oesophageal atresia in 9; intelligence ranges from normal to profound impairment, without predictability from the variant type or the ocular involvement [26]. OTX2 is associated with a variable ocular spectrum with hypopituitarism independent of ocular severity, developmental delay, joint laxity, hypotonia and seizures in some patients [13]. Boys with SOX3 alterations have isolated GH deficiency or CPHD, frequently with adenohypophyseal hypoplasia, an ectopic posterior pituitary and an absent or hypoplastic infundibulum, sometimes with callosal anomalies and intellectual disability [14, 33]. In Webb-Dattani syndrome, the six children of the Saudi family presented at 2–10 days with hypernatraemia due to AVP-D and cortisol insufficiency, without hypoglycaemia, with central hypothyroidism in 4, secondary microcephaly (−3.4 to −6.4 SD), severe global delay, seizures, spastic cerebral palsy at level V of the Gross Motor Function Classification System (GMFCS), absent response to light with a preserved electroretinogram and attenuated visual evoked potentials, and hydronephrosis, vesicoureteric reflux and neurogenic bladder in all; three died of sepsis at 1.2, 4.2 and 5 years [43]. A 17-year-old girl with the same syndrome had panhypopituitarism with AVP-D and adipsia, recurrent hypernatraemia, visual impairment, renal anomalies, neurogenic bladder and spastic quadriplegia, and died at 17 years (Alyami 2025) [15]. SOD with limb and digit anomalies has been described in 4 previous reports with 5 patients and in a new Irish case, with malformations overlapping those of the amniotic band sequence [55]. Harrison's Irish case had syndactyly of several fingers and toes, hypoplastic digits and ring constriction of at least one finger, with a normal hypothalamo-pituitary axis, and Stevens and Dobyns (2004) described a boy with SOD and multiple limb defects suggestive of amniotic bands, which they used as evidence of vascular pathogenesis; the OMIM clinical synopsis records supernumerary and hypoplastic digits [8]. The patients with bilateral ONH and inherited SOX2 missense variants (p.Gly130Ala and p.Ala191Thr) had absent septum pellucidum and, in one of them, neonatal hypoglycaemia and GH, TSH and ACTH deficiencies, that is, a picture of SOD without anophthalmia (section 2.5) [23].

3.8. Other manifestations and occasional anomalies

Occasional anomalies include cleft lip and/or palate, strabismus, autism, learning difficulties, attention deficit hyperactivity disorder, micropenis and cryptorchidism [5]. Webb and Dattani also mention precocious puberty, obesity, anosmia, sensorineural deafness and cardiac anomalies [6]. In the Manitoba cohort, mood and anxiety disorders had an OR of 1.7 (1.0–2.8), not confirmed in the sibling comparison [4]. Carers of children with ONH have at least mild depressive symptoms in 50% and moderate or worse in 25% (9-item Patient Health Questionnaire, PHQ-9; n=20), with worse quality of life in bilateral ONH and with nystagmus [81].

4. Clinical Recognition and Red Flags

4.1. When to suspect, by age

In the prenatal period, absence of the septum pellucidum is detectable on ultrasound from 20 weeks, and fetal MRI is recommended when ultrasound raises suspicion, including to identify SOD-plus [54]. A registry of fetal optic chiasm screening at 16–20 weeks (NCT05717855, completed in 2021 with 52 participants) has no results that would allow such screening to be recommended [82]. In the newborn, SOD should be considered in the presence of hypoglycaemia, jaundice (especially cholestatic), micropenis with or without cryptorchidism and nystagmus, with or without midline anomalies such as cleft palate [6, 33]. In infancy, nystagmus (usual in bilateral ONH) and strabismus (usual in unilateral ONH) are the ophthalmological modes of presentation, and all infants with unilateral or bilateral ONH should be seen by paediatric endocrinology, because the most important association to exclude is endocrine abnormality [65, 72]. Borchert and Garcia-Filion recommend suspecting ONH syndrome in all infants with hypothalamic dysfunction or visual impairment [51]. In childhood, late presentation is with growth failure and mild visual changes [6]. In the presence of corpus callosum agenesis with ONH or absent septum pellucidum, the whole hypothalamo-pituitary axis should be investigated and the MRI reviewed for another midline anomaly [36]. In short stature with subnormal growth velocity and normal initial tests, endocrine investigation for GH deficiency and pituitary imaging are the responsibility of paediatric endocrinology [83].

The history should include consanguinity, sensorineural deafness, developmental delay, anosmia, other anomalies (cardiac, oesophageal atresia, micropenis), seizures (excluding hypoglycaemia), stereotypies or autism, sleep disturbance, excessive appetite, thermal instability and symptoms of hormone deficiencies (fatigue, polyuria and polydipsia, constipation, dry skin, hair loss, sweating) [6]. Oxford Desk Reference adds a three-generation family tree with questions directed at visual problems, exposure to alcohol and anticonvulsants, maternal diabetes and developmental milestones, and on examination short stature, micropenis and facial dysmorphism [65].

4.2. Emergency signs

Cortisol deficiency is what kills: ACTH deficiency may be clinically silent until an intercurrent illness precipitates a crisis, and a child with SOD or ONH without formal assessment of the hypothalamo-pituitary-adrenal axis should be treated as at risk [9]. In the five children with SOD and sudden death described by Brodsky and colleagues, all had corticotropin deficiency and altered thermoregulation, four had AVP-D, and in at least four the deterioration was precipitated by fever and dehydration from a presumed viral illness that appeared to trigger an adrenal crisis [79]. The warning signs are therefore hypoglycaemia, lethargy, vomiting, hypothermia or fever, hyponatraemia and shock [33, 39]. In ACTH deficiency of central origin, electrolyte abnormalities are less frequent than in primary insufficiency, because the renin-angiotensin-aldosterone axis is intact, and hyponatraemia without hyperkalaemia is the most common pattern [54]. In secondary adrenal insufficiency, cortisol deficiency reduces free water clearance and contributes to hyponatraemia [39]. Cortisol deficiency may mask AVP-D, which becomes apparent after glucocorticoid is started [33]. Hypernatraemia, with or without adipsia, is the emergency of AVP-D, especially in Webb-Dattani syndrome [15, 43]. In carriers of SOX2 variants with dystonia, any major physiological stress can trigger status dystonicus, which requires intensive care [26]. Oesophageal atresia with or without tracheo-oesophageal fistula is a neonatal surgical emergency in SOX2 disorder [26].

4.3. Newborn screening

Newborn screening programmes based on TSH alone do not detect central congenital hypothyroidism (CH); more than half of newborns with central CH have moderate to severe disease (initial free thyroxine, FT4, of 5–10 pmol/L or lower), often with other pituitary deficiencies, and the diagnosis is frequently delayed [40]. The 2021 guideline promoted by the European Reference Network on rare endocrine conditions (ENDO-ERN) suggests adding measurement of total or free T4 to screening, where resources allow, to detect central CH (recommendation 2/++0), and recommends that clinical suspicion with a normal screening TSH should prompt assessment for central CH (2/+00) [40]. The European Thyroid Association guideline (ETA, 2018) recommends considering central hypothyroidism in newborns with clinical features of CH and a low or normal neonatal TSH and screening for it in newborns with hypotonia, prolonged jaundice or signs of congenital hypopituitarism (micropenis with cryptorchidism) [64]. GH can be measured on the newborn screening card: Binder and colleagues, with an ultrasensitive polyclonal enzyme-linked immunosorbent assay (ELISA), proposed a threshold of 7 µg/L with 100% sensitivity and 98% specificity [33]. There is no population newborn screening for SOD or for central cortisol deficiency.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal criteria validated by a scientific society. The clinical criterion used in the series is the presence of at least two of three elements: ONH; pituitary hormone abnormalities; midline brain defects, including agenesis of the septum pellucidum and/or corpus callosum [5, 6, 36]. The series operationalise it differently: in Michigan, the third element included agenesis or hypoplasia of the septum pellucidum and/or corpus callosum, and Australian surveillance accepted optic nerve hypoplasia or aplasia, hypopituitarism or anomalies of the septum pellucidum or corpus callosum [32, 71]. Because the deficiencies evolve, a child with ONH and a midline defect without hormone deficiency meets the criterion, and a child with isolated ONH may come to meet it when a deficiency appears [3, 74]. CPHD is defined as deficiency of GH and of at least one other pituitary hormone (TSH, LH and FSH, PRL or ACTH) [28].

5.2. Ophthalmological assessment

The assessment looks for unilateral or bilateral strabismus and nystagmus and the signs of ONH (double-ring sign, pale and/or small disc, reduced neuroretinal rim area), as well as nerve dysplasia, microphthalmia and coloboma, and quantifies the visual impairment [6]. It should distinguish ONH from optic atrophy and from the «crowded» disc of hypermetropia, include refraction and, when necessary, electrophysiology (normal electroretinogram and abnormal visual evoked potentials in ONH) [65]. In a CHLA registry, among 43 patients with orbital MRI and fundus photography before 2 years, a ratio of disc diameter to disc-macula distance (DD/DM) below 0.35 had a sensitivity and specificity of 100% for confirming ONH; nerve diameter on orbital MRI had a moderate correlation with the DD/DM ratio (rs=0.471) and moderate sensitivity; final acuity at 5 years correlated with the DD/DM ratio (rs=−0.869), and fundus photography remains the diagnostic and prognostic reference [37]. OCT allows acuity to be estimated and field defects to be located in cooperative children [73]. When OTX2 is suspected, ocular biometry and ultrasound and an electroretinogram for retinal dystrophy are added [13].

5.3. Neuroimaging

Brain and pituitary MRI is indicated in all suspected or confirmed cases of congenital hypopituitarism, with 2–3 mm slices and high-resolution T1 and T2 sequences in the coronal and sagittal planes, describing the dimensions of the adenohypophysis, the location and size of the posterior pituitary, the stalk, the chiasm, the septum pellucidum and the corpus callosum [33]. The Webb and Dattani list also includes schizencephaly, cavum septi, cerebellar hypoplasia and aplasia of the fornix [6]. The posterior pituitary bright spot is absent in 10% of healthy individuals, which limits the interpretation of this sign on its own [33]. The table summarises the hypothalamo-pituitary anomalies in the GOSH cohort [3].

The stalk percentages in the MPHD group were recalculated from the published numerators and denominators (the article gives 25.4% and 10.4%, inconsistent with 11/49 and 10/49) [3]. Half of the isolated ONH cases and 73% of SOD− patients had a small adenohypophysis with preserved function after median follow-up of 10.22 and 6.20 years; in AVP-D, the posterior pituitary was absent in 65.4% of patients with SOD [3]. Brain MRI is not a reliable screen for the risk of hypopituitarism: in the prospective CHLA cohort (146 children with ONH before 24 months), brain malformation (74%) was not associated with hypopituitarism (positive predictive value, PPV, 71%, 95% CI 62–80%; negative predictive value, NPV, 37%, 95% CI 22–54%), but all 13 patients with a pituitary malformation had hypopituitarism (PPV 100%, NPV 34%) [70]. In an earlier study of 55 patients with ONH, Birkebaek and colleagues classified MRI by the septum and the hypothalamo-pituitary axis: multiple hormone deficiency occurred in 56% when both were abnormal, in 35% with an abnormal axis and normal septum and in 22% with an abnormal septum and normal axis, and no patient with both normal had endocrine dysfunction; precocious puberty was more common with an abnormal septum and normal axis [8]. The two series agree that it is pituitary anatomy, and not septal anatomy, that is best associated with hypopituitarism, and neither removes the need for endocrine surveillance. In PSIS, stalk agenesis predicted progression to CPHD in 87.5% versus 33.3% in stalk hypoplasia (p=0.013), all AVP-D occurred in patients without a visible posterior pituitary, and ONH was strongly associated with progression to CPHD [84]. The chiasmal «Y» sign on coronal MRI was present in 55.1% of 78 patients with ONH and in none of 70 controls, was more likely before 1 year of age and in bilateral ONH, and was not associated with acuity or endocrine abnormalities [85].

5.4. Endocrine assessment

All axes should be assessed, including the posterior pituitary, with follow-up by paediatric endocrinology [9, 36]. Interpretation in the newborn requires specific thresholds, and GH stimulation tests and water deprivation are contraindicated in the neonatal period [33].

The GeneReviews entry on PROP1-related CPHD gives a GH threshold in stimulation tests written as «<7 ng/dL»; the correct unit is ng/mL (µg/L), and stimulation thresholds depend on the assay, so local laboratory values take precedence [28, 33]. The Pediatric Endocrine Society (PES) guideline on GH and IGF-1 (Grimberg 2016) is the North American reference for the diagnosis of GH deficiency in children [87]. It dispenses with stimulation testing when auxological criteria, a hypothalamo-pituitary defect (major congenital malformation, such as an ectopic posterior pituitary (EPP) with pituitary hypoplasia and an abnormal stalk, tumour or irradiation) and deficiency of at least one other pituitary hormone coexist (conditional recommendation, low evidence), and in the newborn with hypoglycaemia whose GH does not exceed 5 µg/L and who has another pituitary deficiency and/or the imaging triad, a criterion matching that of the GOSH review in the table above; after the first week there are no validated neonatal GH thresholds, and a low GH during spontaneous hypoglycaemia is not sufficient on its own outside this context [33, 87]. Among 44 patients with congenital GH deficiency, no newborn with isolated deficiency had hypoglycaemia, versus 60–70% of those with panhypopituitarism [87]. In the remaining cases, the PES recommends not using the tests as the sole criterion (strong) and requires an inadequate response to two different tests, which may be performed sequentially on the same day [87]. In organic deficiency the peaks are very low: median of 2.7 µg/L in 1071 patients in the GeNeSIS registry with any imaging abnormality and mean of 3.1 µg/L (imaging abnormalities, excluding hypoplasia), 4.9 µg/L (pituitary hypoplasia) and 6.6 µg/L (idiopathic deficiency) in KIGS [87]. 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 the North American NCGS registry (236 prepubertal children), height score gains above 1.5 SD in the first year occurred only with peaks below 5 µg/L and the specificity of the 10 µg/L threshold was estimated at 25% [87]. The PES recommends assays harmonised with the somatropin standard IRP IS 98/574 (strong), because differences between assays misclassified up to 29% of patients, and notes that the response decreases with BMI, without validated adjusted paediatric cut-offs, and that untreated hypothyroidism falsely lowers GH [87]. For priming (prepubertal boys over 11 years and girls over 10 years, with a predicted adult height within −2 SD), it proposes 2 mg of oral β-oestradiol (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 [87]. The PES advises against (strong) measuring spontaneous GH secretion for diagnosis, because of overlap with normal children and poor reproducibility; the neurosecretory dysfunction described in the GOSH cohort, defined by a nocturnal profile, corresponds to a practice that this guideline does not adopt [3, 87].

5.5. Genetic testing

Genetic testing is indicated in the presence of signs of a chromosomal or syndromic diagnosis and, according to the central hypothyroidism guidelines, in all congenital or unexplained cases, to detect risk in relatives and extrathyroidal defects [40, 64, 65]. The options are chromosomal microarray (CMA), gene panels for hypopituitarism or developmental eye anomalies, and exome or genome sequencing; the ETA recommends exome, genome or array-CGH when the panel is negative [36, 64]. When SOX2 is suspected, the strategy is sequencing of the gene and, if negative, targeted deletion/duplication analysis including CMA, or a developmental eye anomaly panel; some intellectual disability panels do not include SOX2 [26]. In SOX2 disorder, the proportion of probands with a detectable variant is about 76% by sequencing, about 24% by targeted deletion/duplication analysis and about 21% by CMA (3% of deletions are below CMA resolution); these proportions describe the distribution of known variants and not the clinical sensitivity of the test [26]. SOX3 duplications and rearrangements are detected by CMA or genome sequencing and may escape the exome [14]. The GOSH cohort of 1765 patients proposed a flowchart to guide genetic analysis according to phenotype, which was not read [38]. The overall yield is low: 4.2% in GOSH SOD, 10% in congenital hypopituitarism in general, 14% in ONH by genome sequencing in Stockholm, and between 80% and 90% of cases of congenital hypopituitarism remain without a molecular diagnosis [3, 33, 38, 61]. A negative test does not exclude a genetic cause: sequencing does not detect small CNVs, deep intronic variants, regulatory rearrangements or low-level mosaicism, and the architecture may be oligogenic or polygenic [14, 26, 62].

The report should state the gene, the transcript with version (for example, NM_003865.3 for HESX1 and NM_003106.4 for SOX2), the c. and p. HGVS notation, zygosity and the class according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria [21]. Heterozygous variants of HESX1, OTX2 and PROKR2 frequently have conflicting or uncertain significance (VUS) classifications in ClinVar; family segregation must be read in the light of incomplete penetrance, because an unaffected parent may carry the same variant [9, 45, 67]. Non-molecular tests (basal and dynamic anterior pituitary function, paired osmolalities, dedicated MRI, ophthalmological examination) are the mainstay of diagnosis and follow-up and do not confirm the gene [9].

5.6. Practical algorithm

When one element of the triad is present, the algorithm derived from the sources is: (1) ophthalmological examination with fundus photography and DD/DM ratio, and electrophysiology when indicated; (2) dedicated brain and hypothalamo-pituitary MRI; (3) assessment of all axes with age-specific thresholds, starting with cortisol and FT4, and blood glucose in the symptomatic newborn; (4) hydrocortisone cover before levothyroxine when the adrenal axis cannot be excluded; (5) CMA and panel or exome/genome, with priority when there is anophthalmia/microphthalmia, consanguinity, a family history, extraocular anomalies or a purely pituitary phenotype; (6) renal ultrasound when papillorenal syndrome (PAX2) or Webb-Dattani syndrome is suspected; (7) periodic endocrine reassessment even with a normal initial assessment [3, 33, 36, 37, 40, 43, 65].

5.7. Prenatal and preimplantation diagnosis

Absence of the septum pellucidum can be seen on ultrasound from 20 weeks, with fetal MRI when suspected; prenatal diagnosis does not predict the degree of visual or endocrine impairment [54, 65]. For fetal ultrasound detection of anophthalmia or microphthalmia without prior risk, the historical GeneReviews entry on the MAC spectrum indicated CMA, SOX2 sequencing and targeted deletion/duplication analysis [88]. With an identified familial variant, prenatal diagnosis and preimplantation genetic testing (PGT) are possible, but severity cannot be predicted by the test [26, 65].

6. Differential Diagnosis

6.1. Comparative table

6.2. Main differentials

The most frequent distinction is from isolated ONH, which is a provisional diagnosis: in the Stockholm cohort, 29% of children with ONH had pituitary deficiency, regardless of laterality, and the authors recommend endocrine follow-up until the end of puberty [74]. Genetic CPHD and PSIS share the ectopic posterior pituitary and abnormal stalk, but in SOD the deficiencies are less frequent and later, AVP-D is relatively more frequent and gonadotropin deficiency coexists with precocious puberty in some patients [3]. Septopreoptic holoprosencephaly has absent septum pellucidum, hypoplasia of the olfactory bulbs and optic tracts and pituitary dysfunction with predominant AVP-D, and the neurological and survival prognosis is worse when SOD is part of a broader defect [5, 29]. In severe bilateral anophthalmia or microphthalmia, SOX2 disorder is the main diagnosis, and OTX2 is distinguished by the absence of oesophageal atresia and dystonia [26]. Kallmann syndrome is distinguished by anosmia and the absence of ONH, but shares genes and may coexist with SOD in the same patient [27]. Tubulinopathies and polymicrogyria with ONH require MRI review by a neuroradiologist experienced in malformations of cortical development [36, 65].

7. Treatment and Risk-Management Strategies

7.1. General principles

There is no cause- or gene-directed therapy; treatment consists of replacement of hormone deficiencies, prevention of adrenal crisis and hypoglycaemia, visual rehabilitation and neurodevelopmental support, by a multidisciplinary team with paediatric endocrinology, paediatric ophthalmology, neurology and developmental medicine, with follow-up at least every six months [5, 6, 9, 36]. The review by Malhotra, Chan and Dattani (2026) supports longitudinal endocrine surveillance, detailed ophthalmological assessment and timely hormone replacement with developmental support [53]. There is no SOD-specific guideline; recommendations come from guidelines for analogous conditions (paediatric adrenal insufficiency, central hypothyroidism, GH deficiency, congenital hypogonadotropic hypogonadism, AVP-D) and from reviews of congenital hypopituitarism, and their application to SOD is an extrapolation from an analogous condition [33, 39–41, 64, 101, 102]. The order of introduction matters: levothyroxine should only be started after adrenal function has been assessed and insufficiency, if present, treated, because it increases cortisol clearance and may precipitate a crisis; GH may unmask hypothyroidism and adrenal insufficiency, and cortisol may unmask AVP-D [28, 33, 40, 103].

7.2. Hypoglycaemia and adrenal crisis

In acute presentation with hypoglycaemia, cortisol and TSH deficiencies must be excluded and treated promptly [33]. The consensus guideline of the British Society for Paediatric Endocrinology and Diabetes (BSPED, 2023), prepared by 16 experts and reviewed by the Society for Endocrinology and patient associations, is the most detailed reference for the child with primary or secondary adrenal insufficiency, including hypopituitarism [39]. At a new presentation, urea and electrolytes, glucose, ACTH, cortisol, renin, aldosterone and 17-hydroxyprogesterone are taken before hydrocortisone, without delaying treatment [39].

The BSPED recommends using the neonatal doses in infants who are very small for gestational age or have poor weight gain [39]. The two sources diverge on the IM dose for 1–5 years (50 mg in the BSPED; 25–50 mg in the GOSH neonatal review) [33, 39]. The Food and Drug Administration (FDA) label for Solu-Cortef® (hydrocortisone sodium succinate) gives, for children, initial doses of 0.56–8 mg/kg/day in 3 or 4 doses (20–240 mg/m²/day) and contains no specific paediatric adrenal crisis doses, which come from the guidelines [106]. The 100 mg hydrocortisone injection is available as sodium phosphate in a 1 mL solution or as sodium succinate powder [39].

On the FDA labels, glucagon is indicated for severe hypoglycaemia in diabetes; the emergency kit dose is 0.5 mg (subcutaneous, SC, IM or IV) in children under 25 kg or, if weight is unknown, under 6 years, and 1 mg above these limits, repeatable after 15 minutes; Gvoke® (SC glucagon) is approved from 2 years (0.5 mg below 45 kg) and Baqsimi® (intranasal glucagon, 3 mg) from 1 year [107–109]. In the European Union (EU), Baqsimi® (2019), Ogluo® (2021) and Zegalogue® (dasiglucagon, 2024) are authorised [110]. The FDA label for generic injectable glucagon (Amphastar, revised in 2026) gives 1 mg SC, IM or IV in adults and children weighing 20 kg or more and, below 20 kg, 0.5 mg or a dose equivalent to 20–30 µg/kg, repeatable after 15 minutes while awaiting assistance [104]. GlucaGen® (glucagon 1 mg, powder and solvent for solution for injection; GlucaGen HypoKit), nationally authorised in Portugal (SmPC approved by INFARMED in August 2023) and discontinued in the USA, gives 0.5 mg in children under 25 kg or under 6–8 years and 1 mg above, SC or IM, with a response expected within 10 minutes, oral carbohydrate after the response and IV glucose if there is no response within 10 minutes; it must not be given as an IV infusion [105, 111]. For the newborn and small infant, the 20–30 µg/kg dose of the FDA label is the only weight-based dose in the labels consulted; application to the newborn with hypopituitarism is a label extrapolation, because the approved indications refer to severe hypoglycaemia in diabetes [104, 105]. The FDA label and the Portuguese SmPC warn that glucagon has little or no effect when hepatic glycogen is depleted, notably in adrenal insufficiency, prolonged fasting and chronic hypoglycaemia, situations in which glucose should be used; in hypoglycaemia due to cortisol deficiency, treatment is IV glucose with hydrocortisone, and glucagon is only a bridge when there is no venous access [33, 39, 104, 105]. The FDA label contraindicates glucagon in phaeochromocytoma and insulinoma [104].

7.3. Maintenance hydrocortisone and sick-day rules

Hydrocortisone is the preferred glucocorticoid in children, because it has fewer effects on growth and bone [33, 39]. Cortisol production in the preterm infant is about 7 mg/m²/day on day 5 and 6 mg/m²/day in week 2 [33].

The sources diverge on the sick-day rule: the BSPED prefers a uniform dose of about 30 mg/m²/day in 4 doses, whereas the summary of product characteristics (SmPC) of Alkindi®, GeneReviews and the GOSH neonatal review use doubling or tripling of the usual dose [28, 33, 39, 113]. In children treated with GH, the lowest safe dose of hydrocortisone should be used so as not to interfere with the response to GH, and the somatropin label calls for monitoring of cortisol and a possible increase in glucocorticoid in patients with known hypoadrenalism [28, 103]. Continuous subcutaneous infusion and prolonged-release formulations are not established in the newborn [33]. Carer education, the adrenal insufficiency card and an injectable hydrocortisone kit are components of management; the BSPED guide and card are available online [39]. For context, the BSPED cites, in adults, a crisis in the following year in about 1 in 12 patients with adrenal insufficiency and death from crisis in 1 in 200; in children, the risk factors are diagnosis at a young age, primary insufficiency, the need for mineralocorticoid and recurrent admissions, with diarrhoea and vomiting as danger situations; between September 2019 and August 2022, the reporting system of the English national health service (NHS England) recorded 83 risk reports (1 severe and 2 moderate harms), with glucocorticoid not given perioperatively, delayed or omitted doses and training failures [39].

7.4. Levothyroxine in central hypothyroidism

The FDA label dose table was written for hypothyroidism in general; its application to central hypothyroidism is an extrapolation within the approved indication [116]. The two European guidelines diverge slightly on the neonatal dose for severe forms (10–15 versus 10–12 µg/kg/day) and agree on starting levothyroxine only with preserved cortisol secretion or under hydrocortisone, and on suggesting glucocorticoid before levothyroxine when central adrenal insufficiency cannot be excluded (2/+00) [40, 64]. In practice, 10–15 µg/kg in mild to moderate cases (FT4 5–15 pmol/L) rapidly produces supraphysiological FT4 [40]. Levothyroxine is given as a crushed tablet with water, breast milk or formula, or as a solution, at the same time and with a constant interval from meals; iron, soya, calcium and anticonvulsants reduce absorption; in congenital heart disease with impending heart failure, the initial dose is about 50% of that recommended; the label contraindicates it in uncorrected adrenal insufficiency and asks for biotin to be stopped at least 2 days before blood tests [33, 40, 116]. A low TSH does not indicate overtreatment; when under- or overtreatment is suspected, TSH, free T3 (FT3) or T3 are measured, and underdosing is likely with FT4 near the lower limit, especially with TSH above 1.0 mU/L and symptoms [40, 64].

7.5. Daily somatropin

Somatropin (recombinant human GH) is started as soon as GH deficiency is identified; in the newborn with persistent hypoglycaemia it may be started from the neonatal period, in the evening, subcutaneously, because it helps recovery from hypoglycaemia and may improve cholestasis [28, 33]. The GOSH neonatal review gives 0.16–0.24 mg/kg per week (22–35 µg/kg/day), with good responses to lower doses (10–20 µg/kg/day) at this age, adjustment by IGF-1 at least three-monthly at the start and monitoring for hypothyroidism and adrenal insufficiency [33].

Genotropin®, Norditropin®, Humatrope®, Saizen® and Zomacton® have national or decentralised authorisations in the EU, whose national SmPCs were not consulted [110]. The FDA labels call for monitoring of cortisol in patients with hypoadrenalism, note that hypothyroidism may become manifest or worsen, require fundoscopy before starting to exclude papilloedema and periodically thereafter, monitoring for slipped capital femoral epiphysis and of patients with previous tumours, and prohibit use for growth promotion with closed epiphyses; absence of response in the first year requires review of adherence, hypothyroidism, malnutrition, advanced bone age and anti-GH antibodies [103, 117]. The GeneReviews entry on CPHD states that, once final height is reached, the dose is reduced to 0.2–0.4 mg/day below 60 years and 0.1–0.2 mg/day above, with IGF-1 between the mean and the upper limit of normal [28]. At transition, the Omnitrope® SmPC recommends continuing treatment until full somatic development (body composition, bone mass, with normal peak bone mass defined by a T-score above −1), and the NutropinAq® SmPC requires reassessment of the deficiency in adulthood, with other deficiencies replaced before testing [86, 121].

The only controlled trial in the ONH population is the CHLA trial (2005–2014; NCT00140413): of 17 children with ONH and untreated GH deficiency, 5 with growth deceleration were treated and those with normal growth velocity were randomised to somatropin (n=5) or observation (n=7) for 3 years; treated children grew on average +0.98 SD in height relative to controls, the effect on weight appeared only after adjustment for initial excess weight (+0.83 SD), there was no significant effect on weight-for-height or BMI, and body fat decreased by 6.1% (4.3% after adjustment); the authors consider the results on body composition and lipids inconclusive [82, 122]. In a case with an Xq26.3-q27.1 duplication including SOX3, levothyroxine followed by somatropin took height from −5.87 SD to −1.78 SD in 2 years (Du 2022) [14].

The PES guideline dose is the reference and the labels in the table are given for comparison: the initial range of 22–35 µg/kg/day (strong, low evidence) matches the FDA labels for Genotropin® and Omnitrope® and has a lower limit below the 25 µg/kg/day of the European SmPCs, and the guideline favours the lowest dose with demonstrated efficacy [87, 103, 121]. It does not recommend titration by IGF-1, for lack of adult height data, but suggests measuring it to check adherence and lowering the dose if it exceeds the laboratory range for age or pubertal stage (conditional); 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 had effects compatible with GH excess, and not maintaining the paediatric dose after growth velocity falls below 2–2.5 cm/year (strong) [87]. In KIGS, patients with multiple pituitary deficiency reached a mean adult height of −0.7 SD (men) and −1.1 SD (women), −0.4 and −0.8 SD from target height, with a mean dose of 0.18 mg/kg/week [87]. The PES recommends reassessing the adrenal and thyroid axes after starting GH when the cause may involve multiple deficiencies, as in SOD, and increasing hydrocortisone and/or levothyroxine in those already treated (strong), because GH reduces the conversion of cortisone to cortisol by 11-beta-HSD1, accelerates cortisol catabolism by CYP3A4 and lowers FT4 through increased peripheral deiodination [87]. It also recommends, at each visit, history and examination directed at intracranial hypertension (about 28 per 100,000 treatment-years, more in organic deficiency), slipped capital femoral epiphysis (73 per 100,000 treatment-years overall) and progression of scoliosis (about 0.2%), and suggests not routinely performing cardiac assessment, absorptiometry or a lipid profile in the treated child [87].

7.6. Long-acting growth hormone

Sources for the table: FDA labels and European Medicines Agency (EMA) SmPCs, Drugs@FDA history, consensus statements by Maniatis (2025) and the Growth Hormone Research Society (2026) [101, 102, 111, 123–130]. Switching from daily GH to a weekly formulation takes place on the day after (at least 8 h after) the last daily injection, and between weekly formulations 7 days after the last dose [101, 123, 125]. The 2025 international consensus recommends adjusting the dose to a mean IGF-1 between −2 and +2 SD (ideally close to 0) and starting with a lower dose, by ideal weight, in obesity, with risk of hyperglycaemia or intracranial hypertension, in severe deficiency, in genetic or chromosomal disorders, in renal insufficiency and with oestrogen supplementation; oral oestrogens may reduce the effect of GH [101]. The trials included few children under 3 years and no continuous glucose monitoring, and the impact of these formulations on glucocorticoid and levothyroxine requirements is unknown [101]. The updated consensus statement of the Growth Hormone Research Society (published on 28 August 2026) considers the effects on glucose similar to those of daily GH, but recommends that, in infants and very young children with severe GH deficiency, hypoglycaemia be monitored at the end of the dosing interval, especially with a history of hypoglycaemia and/or multiple pituitary deficiency, with explicit monitoring and management instructions; congenital deficiency, severe deficiency and multiple pituitary deficiency require an individualised dose; injection-site reactions occurred in 5–42% with the weekly formulations versus 6–25% with daily GH; and all patients on long-acting GH should be included in a registry [102]. These warnings make daily GH the best-documented option in the infant with SOD and hypoglycaemia, although no source formulates it as a recommendation for SOD. Jintrolong® (givopegsomatropin, China 2014) and Pegpesen® (inpegsomatropin, China 2025) have only national approval; Eutropin Plus® was withdrawn in South Korea in July 2023 for demand reasons and Nutropin Depot®, approved by the FDA in 1999, was withdrawn in 2004 [102].

7.7. Desmopressin and arginine vasopressin deficiency

In the neonatal period, the recommended management is fluid therapy alone without desmopressin; very severe AVP-D may require desmopressin and, in some severe cases, a thiazide [33]. Overtreatment is more dangerous than undertreatment (fluid retention, hyponatraemia, cerebral oedema and death), so a low initial dose is used (for example, 1 µg), with monitoring of electrolytes, paired osmolalities and weight, and breakthrough diuresis is ensured before the next dose [33]. Desmopressin should be withheld in the newborn with ACTH deficiency who does not tolerate or absorb hydrocortisone (vomiting), until steroid cover is in place, because of the risk of water intoxication [33]. At all ages, the «escape method» (periodic omission or delay of a dose until diuresis occurs) reduces the risk of dilutional hyponatraemia [52].

The oral lyophilisate and the dilute oral solutions used in infants are not FDA products, and the European national SmPCs were not consulted [111]. In Webb-Dattani syndrome and other forms with adipsia, desmopressin is combined with a prescribed fluid regimen and sodium monitoring [15]. Oxytocin deficiency is possible in AVP-D and its treatment is under investigation [52].

7.8. Gonadotropic axis: minipuberty, cryptorchidism, puberty and fertility

The recommendations on gonadotropin deficiency come from the European Consensus on congenital hypogonadotropic hypogonadism (CHH, 2015), which includes SOD among the associated forms, and from the GOSH neonatal review; their application to SOD is an extrapolation from an analogous condition [33, 41].

Oestradiol doses for pubertal induction are not on the labels: the oral oestradiol label gives 1–2 mg/day for hypo-oestrogenism due to hypogonadism (adult dose), and the Vivelle-Dot® label states that it is not indicated in paediatric patients and calls for monitoring of bone maturation when growth is not complete; pubertal induction with low-dose oestrogens is therefore off-label use, with a consensus dose [41, 140, 141]. The Depo-Testosterone® label refers to low initial regimens with progressive increase and does not establish safety and efficacy below 12 years; the Prometrium® label contraindicates it in peanut allergy and does not indicate it in children [137, 142]. Testosterone does not induce gonadal maturation or fertility, and an increase in testicular volume on testosterone requires reassessment of the axis, because spontaneous reversal occurs in 10–20% of CHH [41]. Neonatal gonadotropins (LH/FSH) are under investigation for micropenis with absent minipuberty [33, 41]. When GH is treated and growth is normal, GeneReviews starts induction at 12–13 years in boys and 11–12 years in girls; with untreated GH, it uses lower doses and a later start to maximise growth [28]. Clomifene is not useful, because it requires an intact pituitary [28].

Central precocious puberty was treated in 7.0% of patients with SOD at GOSH [3]. The SOD sources do not state the agonist or the dose; the FDA label of Lupron Depot-PED® (leuprorelin acetate IM) for central precocious puberty gives, for the monthly formulation, 7.5 mg up to 25 kg, 11.25 mg above 25 up to 37.5 kg and 15 mg above 37.5 kg, with three-monthly (11.25 or 30 mg) and six-monthly (45 mg) formulations, monitoring of suppression with a GnRH test, basal LH or sex steroids 1–2 months after starting and height and bone age every 6–12 months; the warnings include the initial rise in gonadotropins, psychiatric changes, seizures (also in patients with central nervous system anomalies), severe skin reactions and idiopathic intracranial hypertension [143]. Application to SOD is an extrapolation within the approved indication.

7.9. Sleep, hypothalamic obesity, vision and neurodevelopment

According to Webb and colleagues, a therapeutic trial of melatonin for sleep disturbance in SOD is accepted practice in many centres, despite the heterogeneity of secretion profiles, and the article does not give a dose [78]. The only melatonin medicinal product with a European paediatric authorisation identified, Slenyto® (prolonged-release melatonin), is indicated for insomnia in children and adolescents aged 2 to 18 years with ASD and/or neurogenetic disorders with abnormal daytime melatonin secretion and/or nocturnal awakenings, when sleep hygiene measures have been insufficient; the initial dose is 2 mg, increased to 5 mg if the response is inadequate, with a maximum of 10 mg, once daily, 0.5–1 hour before bedtime, with or after food; the effect should be assessed after at least 3 months and maintenance reviewed at least every 6 months, with data up to 2 years of treatment [144]. Application to SOD corresponds to the SmPC category «neurogenetic disorder with abnormal daytime melatonin secretion» only when this abnormality is documented, as in the patients of Webb and colleagues; in the others it is an extrapolation [78, 144]. A trial of melatonin for biological clock dysfunction in ONH (Yale, NCT00825591, completed in 2011, 100 participants) has no results in the registry [82].

The hypothalamic obesity of SOD has no approved pharmacological treatment. Setmelanotide (Imcivree®), a melanocortin 4 receptor agonist, was approved by the FDA on 19 March 2026 for acquired hypothalamic obesity from 4 years of age, and the label expressly excludes other obesities, including those associated with genetic syndromes; the European indication also refers to acquired hypothalamic obesity from 4 years [145, 146]. In the pivotal trial (NCT05774756; 142 randomised patients, 47% adults, 31% aged 12 to under 18 years and 23% aged 4 to under 12 years; 56–60 weeks), the mean change in BMI relative to placebo after 52 weeks at the therapeutic dose was −18.40%, and about 61% versus 5% achieved a reduction of at least 10%; hunger decreased in patients aged 12 years or more (n=110) [145]. The initial dose is 0.5 mg (0.05 mL) once daily for 2 weeks, with maintenance of 3 mg/day SC from 6 years and weight-based doses between 4 and 6 years [145]. Congenital hypothalamic obesity, including SOD and ONH, is being studied in a phase 3 trial (section 7.12). The proposal of αMSH as a therapeutic target is based on an observational study [75].

Visual management includes refractive correction, low-vision services and early intervention by teams experienced in visual impairment, with periodic ophthalmological follow-up [6, 65]. In anophthalmia or microphthalmia of SOX2 disorder, the oculoplastic team uses prostheses and, when indicated, expanders to stimulate growth of the orbit and periorbital tissues [26]. Neurodevelopmental support includes early intervention, augmentative and alternative communication, therapies for autistic traits and paediatric psychiatry [26, 34]. Seizures require exclusion of hypoglycaemia and treatment with standard antiseizure medications [26, 36]. Spasticity is managed by orthopaedics, physical medicine and rehabilitation, physiotherapy and occupational therapy, and status dystonicus is an emergency requiring physiotherapy, hydration and intensive care [26]. Sensorineural deafness in SOX2 disorder is treated with hearing aids, and oesophageal atresia with perinatal surgery [26]. There is no treatment available for prolactin deficiency; puerperal alactogenesis is the only specific consequence [33].

7.10. Comparative regulatory status

GlucaGen® was consulted in INFARMED's Infomed database; the other national authorisations and trade names in Portugal and Brazil (ANVISA) were not consulted.

7.11. Clinical trials

The trials of weekly GH formulations included children with GH deficiency in general, with no published analysis of the SOD subgroup, and the consensus statements do not give confidence intervals for the differences in height velocity [101]. Indirect comparison between these trials is not valid, because the comparators, margins and populations differ [101]. The CHLA trial is small, with randomisation only in the normal-growth subgroup, and does not allow conclusions on metabolic outcomes [122]. The setmelanotide trial in the acquired form does not include the congenital form, and the relative reduction in BMI should be read together with the absolute proportion of patients achieving a 10% reduction (61% versus 5%) [145]. No SOD-specific gene or cell therapy trial was found in ClinicalTrials.gov; absence from the registry does not prove that no research exists [82].

7.12. Developments in the last 6–12 months

In the window from 26 October 2025 to 26 October 2026, the developments are: FDA approval of setmelanotide for acquired hypothalamic obesity on 19 March 2026 (authorisation; does not cover SOD) [145]; the phase 3 trial of setmelanotide in congenital hypothalamic obesity, which includes SOD and ONH, started in September 2025 at centres in the USA and United Kingdom (ongoing trial, no results) [147]; the updated consensus statement of the Growth Hormone Research Society on long-acting GH, published on 28 August 2026, with the warning about trough hypoglycaemia in infants with severe deficiency or MPHD (expert consensus based on trials and real-world data) [102]; FDA approval of somapacitan for SGA, Noonan and idiopathic short stature on 27 February 2026 and the positive CHMP opinion, after re-examination, on 17 September 2026 (authorisation in the USA and opinion in the EU; indications unrelated to SOD) [111, 127]; and phase 1–2 trials in hypothalamic obesity not specific to SOD (bivamelagon, LB54640, RM-718, tirzepatide, phentermine/topiramate and semaglutide) [82]. Publications in the period include the endocrine and ophthalmological review by Malhotra, Chan and Dattani (August 2026), the Manitoba mortality, autopsy and educational outcome data, the seizure series of 107 children, the Stockholm quality of life follow-up, Australian national surveillance, the chiasmal «Y» sign and MRI olfactory quantification [32, 35, 53, 60, 80, 85, 148–150]. A 2026 letter on CRISPR interference in HESX1 haploinsufficiency is a speculative commentary, without its own experimental data, and does not constitute preclinical evidence [151].

7.13. Agents to avoid, perioperative care, pregnancy and transition

Levothyroxine should not be started before adrenal cover; desmopressin should be withheld in the newborn without hydrocortisone cover; GH stimulation tests, water deprivation and the vasopressin test are contraindicated in the newborn; clomifene is ineffective in hypogonadism of pituitary origin; micronised progesterone is contraindicated in peanut allergy [28, 33, 137]. TSH measurement is of no use for monitoring levothyroxine, and biotin interferes with thyroid immunoassays [116]. Oral oestrogens reduce the effect of GH and require review of the levothyroxine dose [64, 101].

Perioperatively, the BSPED defines major surgery as surgery lasting more than 90 minutes and recommends IV hydrocortisone at induction (2 mg/kg, maximum 100 mg; 4 mg/kg in preterm infants and below 28 days) followed by a 24-hour infusion by weight (up to 10 kg, 25 mg; 10.1–20 kg, 50 mg; 20.1–40 kg, 100 mg; 40.1–70 kg, 150 mg; above 70 kg, 200 mg), or boluses of 2 mg/kg every 6 h intraoperatively and 1 mg/kg (maximum 50 mg) every 6 h postoperatively; in severe obesity 50 mg is replaced by 100 mg; the patient should be first on the operating list, with fasting of no more than 6 hours without fluids containing sodium chloride and glucose [39]. For minor surgery, such as dental extraction under local anaesthesia, a sick-day dose is given before and the usual dose afterwards, extended for up to 24 hours if there is pain or malaise [39]. In carriers of SOX2 variants with dystonia, perioperative planning should take account of the risk of status dystonicus [26].

In pregnancy in a woman with central hypothyroidism, the levothyroxine dose should be increased to keep FT4 above the mean or median of the trimester-specific range (1/+00), and the ETA recommends increases also during ovarian stimulation [40, 64]. The 2016 Endocrine Society guideline on hormone replacement in adult hypopituitarism, co-sponsored by the European Society of Endocrinology, the Pituitary Society and the American Association for Clinical Chemistry, applies to adults with SOD and addresses pregnancy specifically: hydrocortisone is the preferred glucocorticoid, with dose increases guided by the clinical course and more often in the third trimester; dexamethasone is contraindicated because it is not inactivated by the placenta; stress-dose hydrocortisone is indicated in the active phase of labour, as for major surgery; FT4 or total T4 should be measured every 4–6 weeks, with levothyroxine increased to maintain pregnancy targets; desmopressin is continued with dose adjustment; and GH should be stopped during pregnancy, because the placenta produces GH and there is no proof of efficacy or safety [152]. For non-pituitary surgery in adults, the same guideline suggests 25–75 mg/24 h of hydrocortisone for 1–2 days in mild to moderate surgical stress and, in major stress, 100 mg IV followed by an infusion of 200 mg/24 h (or 50 mg IV or IM every 6 h); these are adult doses, to be used from transition onwards, whereas in children the BSPED weight-based doses above are followed [39, 152].

In the adult with SOD, the Endocrine Society guideline sets hydrocortisone maintenance at 15–20 mg/day, as a single dose or divided with the larger dose on waking; contraindicates fludrocortisone in secondary adrenal insufficiency; requires suspected crisis to be treated with 50–100 mg of parenteral hydrocortisone immediately; recommends the lowest tolerated dose to reduce metabolic, cardiovascular and bone risk; and recommends an emergency card or bracelet for adrenal insufficiency and for arginine vasopressin deficiency [152]. Levothyroxine is dosed to keep FT4 in the upper half of the reference range, with a mean of 1.6 µg/kg/day in adults, without using TSH to adjust the dose and without liothyronine or thyroid extracts [152]. Adult GH is started at 0.2–0.4 mg/day below 60 years and 0.1–0.2 mg/day above that age, titrated to keep IGF-1 below the upper limit of normal [152]. For diagnosis in adults, an 08:00–09:00 serum cortisol below 3 µg/dL (about 83 nmol/L) indicates adrenal insufficiency and above 15 µg/dL (about 414 nmol/L) makes it unlikely; between these values a corticotropin test is performed, with a peak below 18.1 µg/dL (500 nmol/L) at 30 or 60 minutes as the criterion; sampling takes place 18–24 hours after the last hydrocortisone dose; GH tests are not performed in those with clear GH deficiency and three other documented pituitary deficiencies; and patients with childhood-onset GH deficiency are reassessed as adults [152]. The interactions between replacements are as follows: assess the corticotropic axis before starting levothyroxine, or give empirical glucocorticoid until that assessment; monitor FT4 when starting GH, because GH may reveal central hypothyroidism or increase levothyroxine requirements; test the adrenal axis before and after starting GH in those not on glucocorticoid; treat central hypothyroidism before GH testing; adjust levothyroxine when oestrogen is changed; give higher GH doses to women on oral oestrogen; take into account that oestrogen raises total cortisol through corticosteroid-binding globulin; and monitor for the appearance of arginine vasopressin deficiency after starting glucocorticoid, because adrenal insufficiency may mask a partial form [152]. The levels of evidence for these recommendations are mostly low to moderate, and the guideline addresses adult hypopituitarism in general, without SOD-specific data. The sources consulted do not describe SOD-specific lactation data. At transition to adult services (16–18 years), the BSPED refers to the Society for Endocrinology guidance; GH should be reassessed after final height, with retesting of the deficiency before continuing, lower adult doses and, on weekly formulations, the same IGF-1-guided reduction principles [28, 39, 86, 102, 121]. The PES (2016) is more selective about retesting: it considers GH deficiency persistent, without a new test, when there are three or more pituitary deficiencies of any cause, a documented causal variant or a specific structural hypothalamo-pituitary defect, except ectopic posterior pituitary (strong), because in these patients test failure approaches 100% and IGF-1 may even be normal [87]. It reassesses the axis, after at least one month off GH, when there is only one additional deficiency, isolated idiopathic deficiency, a small pituitary or ectopic posterior pituitary, starting with IGF-1 (conditional) and moving to a stimulation test if it is low (strong); ectopic posterior pituitary with stalk agenesis is associated with persistent deficiency, with a normal stalk the retest tends to be normal, and in these patients the PES advises repeating the assessment more than once during transition [87]. At transition, the ITT with a cut-off of 5.6 µg/L had a sensitivity of 77% and a specificity of 93%, and the PES suggests offering GH for persistent deficiency (conditional), with no defined optimal dose [87].

7.14. Guidelines and divergences between sources

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

Most cases of SOD are sporadic; without a family history, the recurrence risk is below 1% [6, 36]. In isolated ONH, the risk is low, with rare reports of dominant inheritance, and recurrence may involve more than ONH, for example features of SOD [65].

8.2. Cascade testing, mosaicism and carriers

When a SOX2 case is apparently de novo, the parents should have a detailed ophthalmological examination and molecular testing, ideally with DNA from more than one tissue (for example, leucocytes and buccal mucosa), and a karyotype with FISH if there is a 3q26.33 deletion, to exclude a balanced rearrangement; maternal somatic or germline mosaicism has been documented in 4 families with sibling recurrence and paternal mosaicism in 2, and a minimally affected mother, with isolated hypogonadotropic hypogonadism (heterozygous or with high-level mosaicism), had two affected children after medically assisted reproduction [26]. In HESX1, reduced penetrance means that absence of a phenotype in a parent does not exclude carrier status [9]. In younger siblings of patients with genetic CPHD, early clarification of genetic status allows replacement to be started in time; without testing, growth should be monitored [28]. In families with SOX3, female carriers should be informed of the risk to their male children [14].

8.3. Prenatal and preimplantation diagnosis

With an identified familial variant, prenatal diagnosis and PGT are possible, but severity cannot be predicted from the family history or the test [26, 65]. Without a variant, fetal ultrasound and MRI follow-up can detect absence of the septum pellucidum from 20 weeks, without predicting visual or endocrine function [54].

8.4. Fertility of affected individuals and counselling of minors

Fertility in patients with gonadotropin deficiency can be induced with gonadotropins or pulsatile GnRH, and female fertility does not depend on anti-Müllerian hormone, a low value of which does not indicate diminished ovarian reserve in CHH [41]. Girls with SOX2 variants may have uterine and ovarian anomalies, which are assessed by pelvic ultrasound and/or MRI, especially at puberty [26]. Predictive testing of minors is justified when it changes surveillance or treatment, as in siblings at risk of genetic CPHD [28]. Counselling should include phenotypic variability, the impossibility of predicting the phenotype for dominant HESX1 variants and the evolving nature of the deficiencies [3, 6].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and incidence: what each study measures

The figures are not directly comparable. The West Midlands and Manchester series count children seen in regional services and may include late diagnoses; Olmsted County measures ONH and not SOD, in a small and almost exclusively white population, and cannot be generalised nationally; Australian surveillance measures only those born in a short period and underestimates prevalence, because 40% of children are diagnosed after the first year of life [7, 30–32]. According to the Australian authors, European databases report values from less than 1/100,000 to 1/14,000 births, which may reflect geographical and ethnic variation and different identification methods [32]. A review of 50 years of epidemiology describes a rapidly increasing prevalence [57].

9.2. Geography, ancestry and social factors

In the West Midlands series, prevalence was non-significantly higher in the Afro-Caribbean group (8% of cases versus 2.5% and 6.7% of the West Midlands and Birmingham populations) and the mixed group (9% versus 1.8% and 3.2%) and significantly lower in the South Asian group (3% versus 8.4% and 21%; p=0.004) [7]. In Manchester and Lancashire, standardised incidence ratios were higher in three densely populated urban districts (167%, 192% and 198%) and correlated with unemployment (r=0.49), children in households without income (r=0.47), conceptions (r=0.46) and teenage pregnancies (r=0.44), without spatial or space-time clustering [30]. In Australian surveillance, cases were distributed across all quintiles of socioeconomic disadvantage and 7 of 11 families travelled 20 km or more to the treating hospital, two more than 100 km [32]. No founder variants have been identified in SOD; the recessive forms (HESX1, ARNT2) are concentrated in consanguineous families, such as the Saudi family with Webb-Dattani syndrome [6, 43].

9.3. Data from Portugal and Brazil

The sources consulted contain no epidemiological data from Portugal or Brazil. Brazil contributed the first human variant in the eh1 repressor domain of HESX1, in a patient born to consanguineous parents from São Paulo, and the São Paulo group authored the GeneReviews entry on PROP1-related CPHD [28, 46]. Somatrogon is approved in Brazil according to the Growth Hormone Research Society consensus [102].

9.4. Special populations

In the newborn and preterm infant, immaturity of the axis and the lack of normative values limit testing; GH stimulation tests are contraindicated before 1 year of age, water deprivation is not recommended and desmopressin requires extreme caution [33]. In infants and young children with severe GH deficiency and MPHD on long-acting GH, there is a risk of hypoglycaemia at the end of the dosing interval [101, 102]. Patients with profound visual impairment have a higher frequency of social difficulties and ASD [34]. In Manitoba, patients with ONH or SOD had more specialised educational funding (OR 13.12; 7.06–24.40), more vulnerability on the Early Development Instrument (OR 2.58; 1.09–6.10), more contact with child and family protection services (OR 1.81; 1.22–2.69) and more institutional or foster care at some point (OR 2.10; 1.32–3.35) [149]. Carer burden is high [32, 81].

9.5. European reference networks and patient associations

Endo-ERN (European Reference Network on rare endocrine conditions, which includes pituitary and hypothalamus; https://endo-ern.eu/) promoted the 2021 congenital hypothyroidism guideline; ERN-EYE (rare eye diseases; https://www.ern-eye.eu/) covers ONH and the anophthalmias; ERN ITHACA (congenital malformations and intellectual disability; https://ern-ithaca.eu/) covers the syndromic forms [40]. EURORDIS (https://www.eurordis.org/) represents European rare disease patient associations. FOCUS Families, in the USA, supports families of children with ONH and SOD, with a newsletter and conventions in the USA and Europe (described by NORD at https://rarediseases.org/organizations/focus-families/) [65]. In the United Kingdom, The Pituitary Foundation (https://www.pituitary.org.uk/), the Child Growth Foundation (https://childgrowthfoundation.org/) and MACS, for microphthalmia, anophthalmia and coloboma (https://www.macs.org.uk/), and in the USA the MAGIC Foundation (https://magicfoundation.org/) and the National Federation of the Blind (https://nfb.org/) [26]. The BSPED provides an adrenal insufficiency guide and an emergency card (https://www.bsped.org.uk/adrenal-insufficiency) [39]. GOSH maintains a patient information page on SOD (https://www.gosh.nhs.uk/conditions-and-treatments/conditions-we-treat/septo-optic-dysplasia/).

10. Illustrative Clinical Case

The case was published in 2026 in Clinical Case Reports by Tan and colleagues, from KK Women's and Children's Hospital, Singapore [54]. A girl was born at 40 weeks and 1 day, with Apgar scores of 9/9, asymmetrically small for gestational age (2696 g, 3rd centile, −1.61 SD; length 46.5 cm, −1.58 SD; head circumference 33 cm, −1.15 SD). The mother was a 20-year-old primigravida, a non-smoker, the parents were not consanguineous, there was no family history and fetal ultrasound scans had shown no signs of SOD; physical examination was normal, without dysmorphic features. At 9 hours of life she had symptomatic hypoglycaemia (capillary glucose 2.2 mmol/L), hypothermia of 34.9 °C and lethargy, treated with buccal glucose gel and milk and then IV glucose, with antibiotics for 48 hours and negative cultures. On day 10 she still required a glucose infusion rate of 5.5 mg/kg/min with 189 mL/kg/day of milk, and attempts to wean the infusion caused recurrent hypoglycaemia (below 3.0 mmol/L, nadir 1.6 mmol/L), with occasional hypothermia. On day 9, acholic stools and conjugated hyperbilirubinaemia appeared (direct bilirubin 25 µmol/L, total 242 µmol/L, gamma-glutamyl transferase 528 U/L, AST 29 and ALT 12 U/L).

The critical sample, taken on day 12 during hypoglycaemia on full feeds, showed glucose of 1.6 mmol/L, cortisol below 28 nmol/L, GH of 1.4 µg/L, undetectable insulin and ketones of 0.0 mmol/L. TSH was 4.54 mIU/L with FT4 of 6.9 pmol/L (reference 11.6–28.3), a pattern of central hypothyroidism; LH was 0.2 IU/L and FSH 1.8 IU/L; sodium was 126 mmol/L with potassium of 4.7 mmol/L and corrected spontaneously to 133 mmol/L within 24 hours, the pattern of hyponatraemia without hyperkalaemia of central adrenal insufficiency. Cranial ultrasound on day 13 was normal. MRI showed the ectopic posterior pituitary on the floor of the third ventricle and hypothalamus, with the adenohypophysis in the fossa, and hypoplasia of the right optic nerve and chiasm (figure 2, sagittal T1 sequence: https://pmc.ncbi.nlm.nih.gov/articles/PMC12886194/figure/ccr371985-fig-0002/; figure 3, coronal T2 sequence with the smaller right hemichiasm: https://pmc.ncbi.nlm.nih.gov/articles/PMC12886194/figure/ccr371985-fig-0003/); fundoscopy showed bilateral disc hypoplasia. Cytomegalovirus testing was negative and hepatobiliary scintigraphy normal [54].

With the diagnosis of SOD, glucocorticoid and levothyroxine were started on day 13 (the article does not give the doses); the hypoglycaemia resolved within 2 days, with one episode on day 14, T4 normalised within 4 days and the cholestasis resolved with hormone replacement. The parents were taught about stress dosing with written instructions and the child was discharged on day 21 weighing 2645 g (−3.1 SD). At 1 year and 7 months she weighed 8700 g (−1.5 SD) and measured 70 cm (−3.5 SD), walked unaided and said «papa» and «mama», without evident visual difficulty according to her parents; she was on hydrocortisone, levothyroxine and somatropin, with three-monthly thyroid function tests. Genetic testing was not performed for financial reasons [54].

The case brings together the neonatal warning signs described in the reviews: persistent hypoglycaemia, hypothermia, cholestasis with raised gamma-glutamyl transferase that resolves with hydrocortisone, hyponatraemia without hyperkalaemia and low FT4 with inappropriately normal TSH [33, 40]. The GH of 1.4 µg/L was sampled on day 12, outside the window of the first 7 days for which the GOSH review proposes the 5 µg/L threshold, and the report does not describe a stimulation test, which is contraindicated in the neonatal period; the child was on somatropin at 19 months [33, 54]. The simultaneous introduction of glucocorticoid and levothyroxine is in line with the guidelines, which require adrenal cover before or simultaneously with levothyroxine [40, 64]. The absence of genetic testing is common in practice and, in this sporadic phenotype, the probability of a molecular diagnosis would be low [3, 32]. The management in the report does not replace the guidelines: the absence of doses in the article prevents comparison with the BSPED and ENDO-ERN recommendations [39, 40].

11. Prognosis and Long-Term Follow-Up

11.1. Mortality

Smith describes a cohort of 88 affected individuals, with a median age of 12.4 years (0.3–36.8), with 5 deaths, 3 due to adrenal crisis and 2 due to neurological problems; the figure of 88 matches the West Midlands series of Atapattu and colleagues, but the abstract of that study does not mention the median age or the deaths, and the full text was not accessible, so these figures are attributed to Smith [5, 7]. Brodsky and colleagues described five children with SOD and sudden unexpected death, all with corticotropin deficiency and altered thermoregulation, four with AVP-D, in whom fever and dehydration precipitated the deterioration [79]. At GOSH, 6/144 (4.2%) patients with SOD died (all with ONH), 1/31 (3.2%) with ONH and none of the 50 with MPHD; in no death was endocrine morbidity recorded as the cause, one patient had autonomic dysregulation suggestive of hypothalamic dysfunction and all had complex multisystem phenotypes (cardiac, neurological, skeletal, respiratory), one of them with cardiofaciocutaneous syndrome [3]. In Manitoba (124 patients with ONH or SOD diagnosed between 1990 and 2019, followed until March 2022, with median follow-up of 12.0 years), 6/124 (4.8%) died versus 8/620 (1.3%) controls, with a median age at death of 4.6 years; crude mortality was 3.7 per 1000 person-years (95% CI 1.7–8.3) versus 1.0 (0.5–2.1), with an HR of 3.7 (1.3–10.5) [148]. In the 21 Manitoba autopsies, the most common cause of death was respiratory disease [60]. When SOD is part of a broader brain defect, such as holoprosencephaly, the prognosis for brain function and survival is poor [5]. In Webb-Dattani syndrome, three of six children died of sepsis before 5 years of age [43]. These figures come from cohorts of treated patients, in centres with different experience and periods, and do not estimate lifetime risk.

11.2. Vision, neurodevelopment and quality of life

ONH is non-progressive [65]. In the follow-up of 31 patients with ONH in Stockholm (median follow-up of 8.5 years, from a median age of 7.8 to 16.3 years), the median best corrected visual acuity of the better eye in bilateral cases improved from 0.25 to 0.57 on the decimal scale (p=0.011), without change in refraction or disc parameters, and field defects were frequent; the composite score of the Pediatric Quality of Life Inventory (PedsQL) was 63.6, highest in the physical domain and lowest in the school domain, with a strong correlation with acuity (r=−0.728) [150]. Final acuity at 5 years correlates with the DD/DM ratio measured before 2 years [37]. In neurodevelopment, delay affects 71% of children with ONH at 5 years, more in bilateral disease, and corpus callosum hypoplasia and hypothyroidism are associated with a worse outcome [76]; early intervention attenuates adverse outcomes [51]. Educational and social needs are high throughout childhood [149].

11.3. Endocrine prognosis

Pituitary deficiencies evolve: a normal assessment at diagnosis does not exclude later deficiencies [3, 9]. Only 22.8% of GOSH patients with SOD retained preserved function during follow-up, 90% of those who developed deficiencies had the first by 8.54 years, and AVP-D appeared late (7.13–16.8 years) in 27.6% of SOD+ patients with AVP-D [3]. In PSIS, 47% of patients with an initial isolated deficiency developed additional deficiencies over a median of 5.9 years, with progression to CPHD in 87.5% of those with stalk agenesis [84]. With adequate replacement, height improves on somatropin, even when initial growth is normal [122].

11.4. Surveillance

The intervals derive from guidelines and reviews of analogous conditions and from gene-specific GeneReviews entries; there is no validated surveillance protocol for SOD.

12. Summary and Concluding Remarks

Septo-optic dysplasia is a clinical syndrome defined by at least two of three elements, optic nerve hypoplasia, pituitary hormone abnormalities and midline brain defects, and not a single neuropathological or genetic entity [6, 60]. The complete triad is present in a minority in regional series, ONH is the most constant element and hypopituitarism, of hypothalamic origin, affects most patients over the course of childhood [3, 7]. The incidence in British series is of the order of 8–11 per 100,000 live births, with an association with young maternal age, primiparity and first-trimester bleeding, which supports a vascular disruption sequence in some cases [7, 30].

The molecular class includes HESX1, SOX2, SOX3, OTX2, PROKR2, FGFR1, FGF8, TCF7L1 and ARNT2, with overlap with combined congenital hypopituitarism, holoprosencephaly and Kallmann syndrome; together, these genes explain a small fraction of cases (4.2% in SOD at a tertiary centre), and the architecture of ONH appears polygenic [3, 38, 62]. Genetic testing is most productive in anophthalmia or microphthalmia, consanguinity, a family history and forms with extraocular anomalies, and a negative result does not change surveillance [6, 26].

Management rests on three principles. The first is prevention of death from adrenal insufficiency: ACTH deficiency may be silent, the sudden deaths described were associated with cortisol deficiency, altered thermoregulation and AVP-D, and stress-dose education, the emergency card and injectable hydrocortisone are part of treatment [39, 79]. The second is the order and interaction of replacements: hydrocortisone before or simultaneously with levothyroxine, monitoring of cortisol and thyroid function when starting GH, reassessment of AVP after glucocorticoid and caution with weekly GH in infants with severe deficiency [33, 40, 102]. The third is longitudinal surveillance: deficiencies appear up to adolescence, including late AVP-D, and apparently isolated ONH requires endocrine follow-up until the end of puberty [3, 74].

The visual prognosis is non-progressive and partly predictable from the DD/DM ratio, neurodevelopment is the main source of long-term morbidity and mortality, about 4–5% in recent cohorts, is concentrated in multisystem phenotypes [3, 37, 76, 148]. The main gaps are the absence of validated criteria and surveillance protocols specific to SOD, the scarcity of trials in this population (one small GH trial and one ongoing trial of setmelanotide in congenital hypothalamic obesity) and the lack of epidemiological data from Portugal and Brazil in the sources consulted [122, 147].

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