Opitz GBBB Syndrome (MID1 and SPECC1L)

Literature and regulatory information updated: 1 November 2026.

X-linked MID1-related Opitz G/BBB syndrome (type I) and the former autosomal dominant form (type II), now divided between 22q11.2 deletion syndrome and SPECC1L-related syndrome (Teebi hypertelorism syndrome type 1); includes Teebi hypertelorism syndrome type 2 (CDH11) and the allelic recessive Elsahy-Waters form

0. Initial Reference Table

1. Introduction

1.1 Founding descriptions: BBB syndrome and G syndrome

Opitz G/BBB syndrome is a congenital midline malformation syndrome whose clinical core combines hypertelorism, hypospadias and defects of the larynx, trachea and oesophagus [1, 2]. The history of the entity begins with John M. Opitz, David W. Smith and Robert L. Summitt, who in 1965 presented in abstract form, and in 1969 published in full, the so-called BBB syndrome in three families in which affected males had apparent hypertelorism and hypospadias and affected females had hypertelorism [6]. The designation BBB derives from the initials of the surname of one of the original families, and one of the photographs in Smith's Recognizable Patterns of Human Malformation shows a mother with mild hypertelorism and two sons with hypertelorism and hypospadias from the “B. O.” pedigree [6, 29]. In the same year, Opitz, Frías, Gutenberger and Pellet described G syndrome, or Opitz-Frias syndrome, named after the family in which it was observed: four brothers with hypertelorism, a neuromuscular defect of the oesophagus and swallowing mechanism, a hoarse cry, hypospadias, cryptorchidism, bifid scrotum and, in one of them, imperforate anus, two other brothers having died of aspiration [1, 3]. The mother had subtle hypertelorism and difficulty swallowing liquids until 11 months, when a short lingual frenulum was divided [3].

1.2 Merger of the two syndromes and the debate on inheritance

G syndrome was distinguished mainly by the presence of laryngeal malformations, but the segregation of both presentations in the same family led to their clinical merger, as proposed by Verloes and colleagues in 1989, and to their joint designation as Opitz G/BBB syndrome [3, 5]. Definitive proof of their unity came in 1997, when pathogenic variants in the MID1 gene were found in patients with both phenotypes, with no correlation between genotype and presentation [5, 30]. For decades, inheritance was controversial: Mendelian Inheritance in Man listed G syndrome in the X-linked catalogue from the 3rd to the 7th edition (1971–1986), and Opitz himself requested in 1987 that it be moved to the autosomal dominant catalogue, citing male-to-male transmission and female involvement almost as frequent as male involvement, although usually milder [3]. In 1995, Robin and colleagues demonstrated by linkage analysis the existence of two loci: three multigenerational families linked to marker DXS987 at Xp22 and five families linked to D22S345 at 22q11.2, both with a LOD (logarithm of the odds) score of 3.53 at zero recombination, and the original G family was assigned to the Xp22 locus [3, 31]. The forms came to be designated Opitz G/BBB type I (X-linked) and type II (autosomal dominant) [3].

1.3 Discovery of the genes and reclassification of the autosomal form

In 1997, Quaderi and colleagues identified, by positional cloning in a family in which the disease segregated with an X chromosome inversion, a new gene at Xp22 with a RING finger domain, which they named MID1 (midline 1), disrupted by the inversion breakpoint and mutated in several families [30, 32]. In 2001, Trockenbacher and colleagues showed that the encoded protein is a ubiquitin ligase that targets the catalytic subunit of protein phosphatase 2A (PP2A) for degradation [3, 29]. As for the autosomal form, it was first found that some patients with a clinical diagnosis of Opitz G/BBB had the 22q11.2 deletion, and GeneReviews now includes these cases in 22q11.2 deletion syndrome, alongside DiGeorge, velocardiofacial, conotruncal anomaly face and Cayler cardiofacial syndromes [1, 5]. In 2015, Kruszka and colleagues found by exome sequencing missense variants in the SPECC1L gene, at 22q11.23, in a three-generation family with an Opitz G/BBB phenotype and normal MID1, and in the large family described by Judith Allanson in 1988, which had been used to establish linkage to 22q11.2 [5, 31]. In the same year, Bhoj and colleagues described SPECC1L variants in two families with Teebi hypertelorism syndrome, an autosomal dominant entity described by Ahmad Teebi in 1987 in a four-generation Arab family [5, 22, 29].

1.4 Current nomenclature

In 2019, Bhoj and colleagues reviewed 31 patients with SPECC1L variants and concluded that, beyond the facial similarities, the pattern of anomalies caused by SPECC1L (abdominal wall and diaphragmatic defects, uterine and branchial anomalies, occasional craniosynostosis and aortic root dilatation) differs from that caused by MID1 (male urogenital malformations and laryngeal cleft), and proposed abandoning the designation “Opitz G/BBB type 2” in favour of “SPECC1L-related syndrome” or Teebi syndrome [5]. OMIM adopted this position: entry 145410 (Opitz GBBB type II) was removed, and the autosomal phenotype is treated as Teebi hypertelorism syndrome type 1 (TBHS1, OMIM 145420), considered the same disease; this designation was preferred because differences between the former Opitz type II and type I have been described [3, 11, 13]. Orphanet declared the X-linked and autosomal dominant subtypes obsolete, keeping ORPHA:2745 for Opitz GBBB, which it defines as a rare X-linked syndrome, and ORPHA:1519 for SPECC1L-related hypertelorism syndrome [2, 4]. Since 2023, GeneReviews has used the dyadic name “MID1-related Opitz G/BBB” (MID1-OS), following the proposal by Biesecker and colleagues to combine gene and phenotype, and considers the designations hypospadias-dysphagia syndrome, Opitz-Frias syndrome, telecanthus with associated anomalies and hypertelorism-hypospadias syndrome obsolete [1].

1.5 Definition of the entities in this article

This article covers the Opitz G/BBB class uniformly and distinguishes three entities, to which Teebi hypertelorism syndrome type 2 is added. The first is MID1-related Opitz G/BBB, defined by the presence of suggestive findings in a boy with a hemizygous pathogenic or likely pathogenic variant in MID1 [1]. The second is SPECC1L-related syndrome (TBHS1), autosomal dominant, which corresponds to most of the families formerly labelled autosomal dominant Opitz G/BBB and is delimited by the SPECC1L variant [3, 5]. The third is the subgroup of patients with an Opitz phenotype and a 22q11.2 deletion, addressed here only in the differential diagnosis and counselling [1, 6]. Teebi hypertelorism syndrome is itself genetically heterogeneous: type 2 (TBHS2, OMIM 619736), described by Li and colleagues in 2021, is caused by heterozygous missense variants in the CDH11 gene, at 16q21, and is covered in dedicated subsections, together with Elsahy-Waters syndrome, the allelic recessive form of the same gene [7, 8, 13]. Also mentioned are the MID2 gene, implicated in a single family with mild Opitz syndrome, and oblique facial cleft type 1, allelic to SPECC1L and still provisional in OMIM [5, 11, 33].

2. Molecular Genetics and Pathophysiology

2.1 The MID1 gene and the midline-1 protein

MID1 is located at Xp22.2 (GRCh38 coordinates X:10 445 310–10 833 683), has nine coding exons and variable 5' untranslated regions, controlled by widely separated alternative promoters; the gene spans at least 400 kb and generates at least six mRNA isoforms [1, 32]. It encodes a protein of 667 amino acids, midline-1 (also called midin or TRIM18), which belongs to the TRIM (tripartite motif) or RBCC family: a RING finger domain, two zinc-finger B-box domains, a coiled-coil domain, a fibronectin type III (FNIII) domain and a carboxy-terminal B30.2 (SPRY) domain [32, 34, 35]. Midline-1 associates with microtubules throughout the cell cycle, on cytoplasmic fibres in interphase and on the mitotic spindle during mitosis and cytokinesis, and forms homodimers and large multiprotein complexes [1, 32]. It functions as an E3 ubiquitin ligase: it monoubiquitinates the IGBP1 protein (alpha-4 regulatory subunit), which exposes the catalytic subunit of PP2A (PP2Ac) to polyubiquitination and proteasomal degradation [3, 11]. Trockenbacher and colleagues showed, in an embryonic fibroblast line from a fetus with Opitz G/BBB, that loss of MID1 function causes marked accumulation of PP2Ac and hypophosphorylation of microtubule-associated proteins [3]. The MID1/alpha-4 complex also forms the core of a microtubule-associated ribonucleoprotein complex that links mRNA transport and translation to the mTOR/PP2A pathway [5, 32].

2.2 Expression and midline pathophysiology

In the human embryo, MID1 is strongly expressed in the central nervous system, especially the rhombencephalon, in the epithelia of the gastrointestinal tract and respiratory tree, in the metanephros, in the anal folds and in a small area of the interventricular septum, and in the mouse it is expressed in undifferentiated cells of the nervous, digestive and urogenital systems [32]. It is also expressed in a subset of cranial neural crest cells that migrate to the branchial arches and the frontonasal process [5]. The consistency between this expression pattern and the malformations of the syndrome supports the interpretation of the disease as a failure of the control of cytoskeleton-associated signalling during development of the ventral midline (face and palate, larynx, trachea and oesophagus, heart, genital tubercle, anus, corpus callosum and cerebellar vermis), and not as a metabolic or degenerative disease; there is no biochemical marker of the deficiency in blood or urine [11, 36]. The Oxford Desk Reference uses Opitz G/BBB as an example of a malformation due to failure of cell migration [36]. MID1 was the first gene described as subject to X inactivation in humans while escaping that inactivation in the mouse, where it lies in the pseudoautosomal region of Mus musculus [11, 32]. Another described function is a role in axonal development [6].

2.3 Spectrum of MID1 variants

Pathogenic MID1 variants include missense, nonsense, small deletions and insertions, intronic splicing variants and duplications, distributed throughout the gene but more concentrated in the 3' portion [1, 37, 38]. Whole-gene deletions and single-exon deletions and duplications have been described: duplication of the first exon (Winter 2003), a 57 kb tandem duplication involving exon 2 that adds 32 amino acids to the start of the coiled-coil domain in a 2-month-old infant with a very mild phenotype, and a complex rearrangement of the exon 6 region with two deletions, an inversion and a small insertion [1, 39, 40]. In the review by Li and colleagues, 184 cases of X-linked Opitz syndrome with a confirmed variant (including 53 females) corresponded to 88 different variants [33]. Splicing variants pose a particular problem, because MID1 is not expressed in blood and mRNA studies are not readily accessible; Micale and colleagues used minigene assays to show that the de novo variant NM_000381.4:c.1286-10G>T, found in a 2-year-old boy, includes eight nucleotides and shifts the reading frame, and that the variants c.864+1G>T and c.1285+1G>T produce in-frame deletions, which allowed the three to be reclassified from uncertain significance to likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria [41]. The variant NM_000381.4:c.1285+1G>T (p.?), known to alter splicing of exon 5, was the one found in the newborn described by Spinelli and colleagues [10, 18].

The variants c.1656del and c.1215_1228dup are given as in the original article, which does not state the reference transcript; the other point variants were validated in VariantValidator on the MANE transcript NM_000381.4 [10, 45]. The article by Wang and colleagues describes the p.(Leu292Pro) variant as frameshift, but the c.875T>C change is a missense substitution [10, 42]. The abstract by Yan and colleagues describes the c.1483C>T variant as homozygous in a boy, whereas on a single X chromosome the correct designation is hemizygous [43].

2.4 Disease mechanism and genotype–phenotype correlation

Missense and truncated forms of midline-1 lose affinity for microtubules, and the likely mechanism is loss of ubiquitin ligase function at the cytoskeleton [1, 38]. Homodimerisation capacity is retained in several mutant forms, whereas association with microtubules is impaired [32]. In general, there is no correlation between variant type and phenotype, which is highly variable even within a family [1]. Maia and colleagues, from Porto, analysed 91 boys with X-linked Opitz syndrome and found no statistically significant association between variant type, affected domain or impaired function and the major findings (hypertelorism, orofacial clefts, laryngotracheo-oesophageal defects, hypospadias and intellectual disability) or minor findings (brain, cardiac and anal anomalies) [45]. Two exceptions have been proposed: Fontanella and colleagues observed a preferential association between truncating variants and anatomical brain defects, mainly cerebellar, and Mnayer and colleagues, based on a man of above-average intelligence with the P441L variant (historical numbering, = NM_000381.4:c.1322C>T p.(Pro441Leu)) in the FNIII domain, suggested that missense variants in that domain give milder phenotypes and that all truncating variants give severe phenotypes [1, 34, 38]. The review by Li and colleagues did not confirm the association with the FNIII domain, having found three cases with point variants in that domain and a phenotype that was not mild [33]. So and colleagues pointed to a possible correlation only for laryngotracheo-oesophageal malformations [46].

2.5 Penetrance, expressivity and heterozygous females

In boys, the presence of a pathogenic MID1 variant is usually accompanied by clinical manifestations [1]. Expressivity is highly variable: Hüning and colleagues stressed that MID1 alterations may go unnoticed in individuals who do not meet the minimum criteria for a clinical diagnosis, which favours a genotype-first approach [39]. Most heterozygous females have isolated hypertelorism; in the compilation by Li and colleagues, 38 of 42 had hypertelorism and none had an orofacial cleft, hypospadias, heart disease or anal anomaly [1, 33]. Rarely, they present with anteverted nares, a short nose, a short uvula, a high-arched palate, micrognathia, tracheo-oesophageal cleft, oesophageal stenosis or anal malformation [1]. There were lethal female cases in the original G family, and a 43-year-old symptomatic heterozygous woman had a pituitary macroadenoma and a cranial osteoma [3]. The sources consulted do not quantify the role of the X-inactivation pattern in female variability.

2.6 Allelic disorders and other genes

No other phenotype associated with MID1 variants is known [1]. The identification of MID1 variants in fewer than half of clinical cases of X-linked Opitz syndrome and the intrafamilial variability suggest the involvement of other genes [33, 37]. MID2 (Xq22), a paralogue of 685 amino acids with 83% similarity (76% identity) to MID1, has been implicated in a single family with mild Opitz G/BBB, according to Li and colleagues and Bhoj and colleagues, who cite Geetha and colleagues [5, 33]. The interaction of midline-1 with IGBP1, whose gene is located at Xq13, led Trockenbacher and colleagues to speculate on a role for that gene in FG syndrome [3].

2.7 The SPECC1L gene and the related syndrome

SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) is located at 22q11.23 (GRCh38 22:24 270 831–24 417 738) and encodes a cytoskeletal protein that links actin and microtubules [5, 11, 47]. The protein stabilises acetylated microtubules, colocalises with acetylated alpha-tubulin at the mitotic spindle, at cell junctions and near the microtubule-organising centre, and reorganises the actin cytoskeleton through its carboxy-terminal domain [47]. Its deficiency in cell culture impairs adhesion and migration, with fewer F-actin microspikes and filopodia and an inability to reorganise actin in response to calcium or WNT5A [47, 48]. In the mouse, Specc1l is expressed in the maxillary prominence and lateral nasal process between E9.5 and E10.5; loss of the gene increases adherens junction stability and reduces delamination of cranial neural crest cells, through a mechanism mediated by PI3K-AKT signalling, and homozygous loss-of-function mutants die during the embryonic period with defective neural tube closure [5, 49]. In zebrafish, knockdown of a homologue produces a phenotype lacking facial structures [48].

The clinical consequences depend on the mechanism. Haploinsufficiency is documented in oblique facial cleft: a de novo translocation t(1;22)(q21.3;q11.23) disrupts intron 14 of SPECC1L in a girl with bilateral oblique clefts of the oro-medial-canthal type, and a de novo missense variant NM_015330.6:c.1244A>C p.(Gln415Pro) was found in a Brazilian infant with a severe right Tessier type 4 cleft and a mild left type 7 cleft, without other malformations, among 23 patients screened [5, 47, 48]. Oblique facial clefts account for about 0.25% of facial clefts; the association with SPECC1L (oblique facial cleft type 1, OMIM 600251) rests on two patients, is flagged as provisional in the OMIM gene–phenotype table, and G2P classifies it as disputed evidence [11, 14, 47]. In Teebi syndrome, by contrast, none of the 31 patients compiled by Bhoj and colleagues had a Tessier 4 cleft, which suggests a mechanism other than haploinsufficiency for the missense variants [5]. These cluster in two domains of the protein, around codons 397–461 and 1009–1098, and the mutant proteins T397P and G1083S form punctate aggregates and stabilise microtubules poorly [5, 47, 50]. In 2025, the first intragenic SPECC1L deletion was described, removing exon 3 with the canonical start codon in two relatives with a compatible phenotype; expression assays showed use of an alternative start codon and a truncated protein, which extends the spectrum to structural variants [23].

The variants published by Bhoj and colleagues on NM_015330.4 retain the same numbering on the MANE transcript NM_015330.6, according to the validation performed in VariantValidator for c.1189A>C, c.1258G>A, c.3247G>A and c.3293G>A [5, 10]. SPECC1L is also a recurrent partner of somatic fusions with ALK, NTRK and MET in tumours, events with no germline significance [11].

2.8 Biological convergence between MID1, SPECC1L and actins

MID1, SPECC1L and the cytoplasmic actin genes (ACTB and ACTG1, which cause Baraitser-Winter syndrome) share functions in the cytoskeleton of neural crest cells, which explains the facial similarities (hypertelorism, broad and short nose, orofacial clefts), but each gene has its own specific features: SPECC1L is involved in branchial morphogenesis, diaphragm development, closure of the umbilical ring and fusion of the Müllerian ducts, structures rarely affected in the other syndromes [5]. In 2026, a mouse model with conditional deletion of Specc1l in neural crest cells reproduced the short skull, reduced frontal bone, nasal defects and midface hypoplasia, with shortened primary cilia and increased Hedgehog signalling from E9.5; this is preclinical evidence [51].

2.9 The CDH11 gene, Teebi hypertelorism syndrome type 2 and Elsahy-Waters syndrome

CDH11, at 16q21 (OMIM 600023; MANE transcript NM_001797.4, protein NP_001788.2), encodes cadherin-11, also called osteoblast cadherin (OB-cadherin) because it was isolated from a murine osteoblastic cell line and from a human osteosarcoma [7, 8]. It is a classic type II cadherin, defined by the absence of the histidine-alanine-valine (HAV) motif in the first extracellular domain, and has 796 amino acids organised into a signal peptide, a propeptide, five extracellular repeats of about 110 amino acids (EC1 to EC5), a transmembrane domain and a cytoplasmic domain that links the catenins to the actin and microtubule cytoskeleton [8]. Cadherin-11 forms two types of dimers: cis dimers on the same membrane, which depend on extracellular calcium binding to the linker regions between EC domains, and trans dimers between neighbouring cells, formed by the EC1 domain, in which the anchor tryptophan residue (Trp55 in precursor numbering, W2 in the mature protein) is essential [8, 21]. During the epithelial–mesenchymal transition of cranial neural crest cells, type I cadherins (CDH1, CDH2) decrease and cadherin-11 increases; migration of these cells to the branchial arches requires a fine balance of cadherin-11-mediated adhesion [8]. In human embryos of 67 to 72 days, the protein is strongly expressed in the facial mesenchyme, the central palatal and dental mesenchyme, the eye and ocular muscles, and the tongue, which matches the distribution of the manifestations [8].

The same gene causes two diseases with different inheritance patterns, and both patterns are recorded in OMIM and Orphanet. Teebi hypertelorism syndrome type 2 (TBHS2, OMIM 619736) is autosomal dominant and results from heterozygous missense variants in the extracellular domains [7, 8]. Elsahy-Waters syndrome, or branchioskeletogenital syndrome (OMIM 211380, ORPHA:1299), is autosomal recessive and results from biallelic loss-of-function variants, mostly truncating, that eliminate the transmembrane and intracellular domains [9, 12, 52–54]. In 2021, Li and colleagues described TBHS2 in 19 individuals from nine families (A to I), brought together by a consortium led by the Children's Hospital of Philadelphia with centres in the United States, Italy, Spain, Canada, Belgium and Australia, through research or clinical exome sequencing with Sanger confirmation [8]. Nine different missense variants were identified, all absent or rare in population databases and located at residues conserved across vertebrates and in other classic cadherins; in OMIM, the variants arose de novo in five of the nine families, and the Australian family had six affected members carrying the same variant [7, 8].

All notations were confirmed in VariantValidator on the MANE transcript. Kuroda and colleagues give the p.(Leu77Phe) variant with the coordinate NC_000016.9:g.64998856G>A, but that position corresponds to the GRCh38 assembly (NC_000016.10:g.64998856G>A); on GRCh37 the coordinate is NC_000016.9:g.65032759G>A [10, 21]. The abstract by Li and colleagues places six variants around the EC2–EC3 and EC3–EC4 linkers, whereas the results of the same article place them near the EC1–EC2 and EC2–EC3 linkers; the table follows the residue positions [8].

The functional studies used L cells, murine fibroblasts without endogenous cadherins, transduced with the normal protein or with the variants in the previous table (NM_001797.4): cells with normal cadherin-11 bound the cadherin-11-Fc fusion protein in a dose-dependent manner, the variants p.(Trp55Ser), p.(Glu140Lys) and p.(Gly327Trp) practically did not bind, and the variants p.(Asp260Asn) and p.(Asn262Ile) bound less, with significant differences at all concentrations tested [8]. In fibroblasts from the individual with p.(Glu279Gln), cadherin-11 was increased, and the cells spread less well, formed membrane blebs and ruffles, had immature focal adhesions without stress fibres and closed an in vitro wound about twice as fast as controls, with no difference in proliferation [8]. The authors propose a dominant negative effect, by analogy with a Xenopus mutant lacking part of the EC1–EC2 domains that accelerated neural crest migration and reduced expression of twist, the orthologue of TWIST1 in Saethre-Chotzen syndrome, but do not exclude loss of function [8]. In Elsahy-Waters syndrome, fibroblasts from the Turkish sisters had no detectable protein, proliferated more slowly and had delayed osteogenic differentiation, which is consistent with loss of function [52]. TBHS2 and Elsahy-Waters syndrome thus constitute a dominant/recessive allelic pair comparable to other genes with dominant negative effects and recessive loss-of-function effects; Kuroda and colleagues suggest that they form a spectrum of CDH11-related disorders [8, 21]. Among the 83,238 tumours in the cBioPortal database there were 1,084 somatic CDH11 variants, but the sources consulted do not describe any cancer predisposition associated with germline variants [8].

3. Clinical Spectrum and Manifestations by System

3.1 Overview and data sources

Clinical knowledge of MID1-related Opitz G/BBB rests on case reports and small series: at its 2023 update, GeneReviews counted about 90 published individuals with a pathogenic variant and a clinical synopsis, and the compilation by Li and colleagues brought together 184 X-linked cases with a confirmed variant, including 53 females [1, 33]. Frequencies depend on how the data were collected: hypertelorism and hypospadias are among the clinical criteria that lead to testing, which inflates their proportions, and series of patients referred to reference laboratories over-represent severe forms [33, 46]. So and colleagues, in a series of 70 patients, observed that carriers of MID1 variants were less severely affected than in earlier reports, especially as regards functionally relevant neurological, laryngotracheo-oesophageal, anal and cardiac anomalies [46]. The following table compares the two reference compilations.

Sources: GeneReviews (Fontanella 2008, Li 2016, Maia 2017, Micale 2023, Perea-Cabrera 2023) and Li and colleagues [1, 33]. ID, intellectual disability.

The table shows that estimates of laryngotracheo-oesophageal defects vary between about 45% and 70% depending on whether only structural anomalies or also functional swallowing disorders are counted; Li and colleagues separated the two groups, whereas De Falco and colleagues found laryngotracheo-oesophageal defects in all the boys with a MID1 variant they reviewed, and Migliore and colleagues, in 12 new patients, placed them among the three most frequent findings, together with hypertelorism and hypospadias [33, 37, 40].

3.2 Face, skull and oral cavity

The facies of affected boys includes a wide fontanelle, a prominent metopic suture, a prominent forehead, a widow's peak (V-shaped hairline at the frontal midline), hypertelorism (with or without telecanthus), a broad nasal root, anteverted nares and low-set, malformed ears [1]. Smith's Recognizable Patterns of Human Malformation adds upslanting or downslanting palpebral fissures, epicanthic folds, a short lingual frenulum, posteriorly rotated auricles and micrognathia, and, as occasional findings, cranial asymmetry, strabismus, a cleft nasal tip, a long, flat philtrum, a thin upper lip, bifid uvula, cleft tongue and dental anomalies [6]. Cleft lip and/or palate, unilateral or bilateral, occurs in about half of boys and is accompanied by feeding difficulties and hearing loss; other oral findings are a high-arched palate, ankyloglossia, hypodontia and neonatal teeth [1]. Hypertelorism should not be confused with telecanthus: the Oxford Desk Reference recommends measuring the inner and outer canthal distances and the interpupillary distance and relating them to head circumference [29].

3.3 Larynx, trachea, oesophagus and feeding

Laryngotracheo-oesophageal defects are the manifestation with the greatest impact on survival. In their most severe form they correspond to laryngeal and laryngotracheo-oesophageal clefts; in the mild form, to tracheo-oesophageal fistula or laryngotracheo-oesophageal dysmotility [1]. They present with coughing and choking during feeds, recurrent pneumonia and potentially fatal aspiration [1]. Smith also describes laryngeal malformation, a hypoplastic epiglottis and a high carina, and points out that swallowing problems with recurrent aspiration, stridulous breathing, intermittent respiratory distress, wheezing and a weak, hoarse cry should raise suspicion of a potentially lethal laryngo-oesophageal defect [6]. The incidence of respiratory and gastro-oesophageal complaints is probably underestimated, because in mild cases there is only a functional swallowing difficulty that improves with age and disappears in early childhood [1]. Robin and colleagues, comparing families linked to Xp22 and to 22q, found that posterior laryngeal cleft was exclusive to the X-linked families [3, 6]. Boys tend to have more frequent and more severe laryngo-oesophageal defects, but the disease can be expressed with equal severity in both sexes [6].

3.4 Genitourinary system

Hypospadias, of variable severity, occurs in about 90% of boys with MID1-OS and is often associated with cryptorchidism and a hypoplastic or bifid scrotum; in severe forms there may be urinary dysfunction with vesicoureteral reflux and hydronephrosis [1]. In girls, widely spaced labia majora have been described [6]. Isolated cases of bladder exstrophy associated with complex heart disease (double outlet right ventricle with pulmonary atresia) and of crossed fused renal ectopia have been described [3, 18, 55]. In 2026, a case was published of a young man with Opitz G/BBB who developed clear cell adenocarcinoma of the urinary tract, a Müllerian-type tumour; this is an isolated report, with no gene stated in the abstract, which does not allow risk to be estimated [56].

3.5 Heart and great vessels

About 24% of boys have congenital heart disease, mainly ventricular septal defect (VSD), atrial septal defect (ASD), coarctation of the aorta, persistent left superior vena cava, patent ductus arteriosus and patent foramen ovale [1]. Smith reports a predominance of conotruncal lesions [6]. Perea-Cabrera and colleagues described two Mexican brothers, born to consanguineous parents, with total anomalous pulmonary venous drainage and subtle facial dysmorphism, carrying the variant NM_000381.4:c.608G>A p.(Arg203Gln); one died at 2 years of cardiopulmonary complications after surgical correction and the other had normal development at 2½ years [35]. The authors note that this heart defect is frequent in the Mexican population and that an ethnic predisposition cannot be excluded [35]. In 2025, Wang and colleagues reported a 33-year-old Chinese man with exertional dyspnoea for 20 years, telecanthus, a 0.6 cm ASD, mild pulmonary hypertension, a left ventricular ejection fraction of 28% and frequent ventricular ectopy (20.29% of beats over 24 hours), without fibrosis on cardiac magnetic resonance imaging, carrying the p.(Leu292Pro) variant, whose brother had cleft lip, ASD and Ebstein anomaly; with standard heart failure therapy, the ejection fraction rose to 46% at 90 days [42]. The authors attribute the ventricular dysfunction to the syndrome, but a single case does not demonstrate causality [42].

3.6 Central nervous system and development

Almost a third of boys with MID1-OS have developmental delay and intellectual disability, with delayed walking, attention deficit, learning difficulties and speech disorders; in some, the delay is secondary to the surgical interventions [1]. Smith, by including both the X-linked and the autosomal forms, gives mild to moderate intellectual disability in about 50% of boys, and hypotonia [6]. Anatomical midline anomalies, such as agenesis or hypoplasia of the corpus callosum and the cerebellar vermis and Dandy-Walker malformation, were found in about half of the boys studied by magnetic resonance imaging, and Pinson and colleagues found hypoplasia or agenesis of the vermis in 4 of 9 patients with a MID1 variant, including one without developmental delay, which justifies looking for it even in the absence of intellectual disability [1, 3]. Other imaging findings described are cortical atrophy, ventriculomegaly, mega cisterna magna, pituitary macroadenoma, cranial osteoma and an enlarged cavum septi pellucidi [6].

3.7 Hearing, vision and other systems

Hearing loss is mainly associated with cleft palate [1]. At the Hospital for Rehabilitation of Craniofacial Anomalies of the University of São Paulo, in Bauru, Cassab and colleagues studied 14 men aged 7 to 34 years with a diagnosis of G/BBB syndrome and repaired cleft palate: 2 (14.3%) had bilateral hearing loss, one moderate (mean 43.7 dB) and the other mild (about 22 dB); tympanometry was normal (type A) in 73% of the 26 ears tested; brainstem auditory evoked potentials showed normal wave I latencies, but increased latencies of waves III and V in 2 and 6 patients and of the I-III, III-V and I-V intervals in 4, 3 and 8, which the authors interpreted as involvement of the central auditory pathway in the brainstem [57]. The abstract of this study gives a proportion of normal audiograms (66.7%) that does not match the detailed results, and the genetic diagnosis is not specified gene by gene [57]. Refractive error and strabismus have been described in the visual domain [1]. Other occasional findings are hernias (inguinal, umbilical and hiatal), diastasis recti, gallbladder agenesis, duodenal stenosis, pulmonary hypoplasia, syndactyly and congenital chylothorax [3, 6, 37]. Monozygotic twinning is unusually frequent in the families, and cases of early lethality often occur in twins [3, 6].

3.8 Heterozygous females

Females heterozygous for MID1 variants usually have only hypertelorism and rarely other anomalies [1]. In the family of Perea-Cabrera and colleagues, the heterozygous mother and sisters had neither hypertelorism nor any other anomaly, and in the case of Spinelli and colleagues the heterozygous mother and aunt had no evident signs [18, 35]. By contrast, a 43-year-old heterozygous woman had telecanthus, anteverted nares, frequent respiratory and urinary tract infections, a pituitary macroadenoma and a cranial osteoma, and lethal female cases have been described in the G family [3].

3.9 Natural history

Mortality in patients with a severe laryngo-oesophageal defect is high if the defect is not repaired and the lungs protected by gastrostomy or jejunostomy [6]. After the initial phase of poor weight gain, survivors grow normally [6]. The sources consulted contain no follow-up series into adulthood with survival, respiratory function, fertility or quality of life; adult data are limited to the Brazilian audiological study, the heterozygous woman with a pituitary tumour, the man with heart failure and the report of a urothelial tumour [3, 42, 56, 57]. GeneReviews does not distinguish frequencies in treated and untreated patients, and the proportions above describe clinically recognised patients, many of whom had undergone surgery [1].

3.10 SPECC1L-related syndrome

The compilation by Bhoj and colleagues brings together 31 individuals (14 male and 17 female) from 12 families, with a mean age of 23 years at last assessment in the 16 observed after the first year [5]. Birth parameters were normal (head circumference −0.17 standard deviations, length +0.08, weight −0.34), but at a mean age of 21 years mean height was −1.56 standard deviations and weight −1.55 [5].

Source: Bhoj and colleagues, table 2 [5]. Rare findings: thyroglossal duct cyst, auditory canal atresia, vertebral hypersegmentation and natal teeth.

The facial phenotype resembles that of X-linked Opitz syndrome, but the laryngeal and male genital malformations are absent, and branchial fistulas, omphalocele, diaphragmatic hernia and bicornuate or didelphic uterus occur [5, 6]. Congenital diaphragmatic hernia, which occurs in about 1 in 2,500 live births in the general population, is a prominent feature: Wild and colleagues brought together six patients with diaphragmatic hernia and a SPECC1L variant, compared with only two boys with a MID1 variant described with this malformation [58]. Bhoj and colleagues in 2015 drew attention to aortic root dilatation and craniosynostosis, and Kruszka's family A included a boy with critical aortic stenosis and post-stenotic dilatation of the aortic root, metopic craniosynostosis, tracheomalacia and hernias [22, 31]. Expressivity is variable within families: in a family with the variant NM_015330.6:c.3293G>A p.(Arg1098Gln), the proband had bilateral cleft lip and palate, diaphragmatic hernia operated on on the first day, severe intellectual disability, absent speech and autism spectrum disorder at 19 years, whereas his mother and grandmother, with bicornuate uterus, had attended school with support and led independent social lives [5]. In another family, a woman with the de novo variant p.(Glu420Lys), a natal tooth, ASD, umbilical hernia, short stature and bicornuate uterus had two pregnancies with female fetuses with severe diaphragmatic hernia, terminated at 22 weeks and at 17 weeks and 3 days [5]. In Teebi's original family, with 16 affected individuals over four generations, intelligence and stature were normal, the men had a shawl scrotum but not hypospadias, and there was umbilical hernia in 2 of 6 described [5]. A second compilation, by Zhang and colleagues in 2020, with 33 patients from 14 families, found hypertelorism in 94%, a broad nasal root in 75%, downslanting palpebral fissures in 42.4%, umbilical defects in 42.4%, bicornuate uterus in 9 of 17 women (53%), heart disease in 27.2%, developmental delay in 24.2% (with some catching up during childhood), diaphragmatic hernia in 21.2%, orofacial clefts in 18.2% and central nervous system defects in 18.2%, according to the OMIM synopsis [13]. The proband of the Allanson family, the first attributed to SPECC1L, had the laryngotracheo-oesophageal manifestations of G syndrome (swallowing difficulties and stridor) and sagittal craniosynostosis, which shows that the absence of a laryngeal cleft does not exclude swallowing symptoms in this syndrome [5, 13, 31]. Han and colleagues described a 4½-year-old child with Teebi syndrome who required a pacemaker for complete atrioventricular block, a unique finding among the cases reviewed [13]. A 2026 report added to the spectrum spina bifida with thoracic myelocele and an intradural dermoid cyst in a 4-year-old child [59].

3.11 Comparison between MID1 and SPECC1L

Source: Bhoj and colleagues, table 3, with the MID1 data compiled by Li and colleagues; Fisher's exact test; ns, not significant [5, 33].

3.12 Form associated with the 22q11.2 deletion

In families with an Opitz phenotype and a 22q11.2 deletion, males and females are affected with equal frequency, and all the manifestations described in the X-linked form have been observed, except anteverted nares and posterior laryngeal clefts [6, 60]. Robin and colleagues described in the 22q-linked families a broader forehead and coarser features, intellectual disability in 25% of carriers, structural laryngotracheal anomalies without a cleft in 2 of 13 men and 1 of 7 women, and hypospadias in 5 of 16 men; Bhoj and colleagues, on reviewing these families, considered that some diagnoses would not meet current criteria [5]. McDonald-McGinn and colleagues described in 1995 patients with a diagnosis of Opitz G/BBB who presented with a vascular ring and had a 22q11.2 deletion, one of them with a mildly affected father carrying the deletion, and proposed that the autosomal dominant form might result from this deletion; previously, a ring chromosome 22 had been found in two patients [13]. The 22q11.2 deletion has its own, broader phenotype.

3.13 Teebi hypertelorism syndrome type 2 (CDH11)

TBHS2 is defined by hypertelorism, a prominent forehead, thick, broad eyebrows and a short nose with a depressed nasal root and broad tip, together with a thin upper lip, a small chin with a horizontal crease and a high-arched or cleft palate; some patients have developmental delay or intellectual disability [7]. The only published cohort is that of Li and colleagues, with 19 individuals from nine families assessed independently by the clinicians at each centre; the data are cross-sectional, without longitudinal follow-up [8]. Hypertelorism was present in all, a broad or high forehead in 18 of 19 (ten with a wide anterior fontanelle), thick or broad eyebrows in 17, a broad nasal tip in 18, a short nose in 15, a depressed nasal root in 13 and a broad or high nasal root in only one [8]. A thin upper lip and a small chin with a transverse crease were present in 16 of 19, a high-arched or cleft palate in 68%, an everted lower lip in 37%, proptosis and ptosis in 5 of 19 each, small teeth and delayed tooth eruption in 16% each, and two patients had a subtle coloboma of the upper eyelid, a finding not previously described in Teebi syndrome [8].

Outside the face, 9 of 18 patients had minor anomalies of the extremities (tapering fingers, short distal phalanges, broad thumbs or halluces, small hands and feet, bulbous toe tips, fifth-finger clinodactyly) [8]. Congenital heart disease occurred in 5 of 19 and umbilical defects in 3 of 13 assessed; hypospadias was recorded in 4 of 8 boys, none with a shawl scrotum, and there were skeletal changes of the trunk (pectus excavatum and vertebral fusions) in a minority, with counts that differ between the text (two patients) and the table (3 of 13) of the article [8]. Development was normal in 12 of 19; of the seven with delay, five had only mild language delay and one had global delay, and autism spectrum disorder and attention deficit hyperactivity disorder were diagnosed only in two members of one family [8]. No patient had craniosynostosis or diaphragmatic hernia, unlike the 19 to 23% of patients with a SPECC1L variant [5, 8].

In 2024, Kuroda and colleagues described a 10-month-old Japanese boy with normal development, hypertelorism, strabismus, hypospadias, shawl scrotum, broad thumbs (bifid on the right on radiography), polysyndactyly of the left fourth finger and cutaneous syndactyly of the left third and fourth fingers, with the de novo variant p.(Leu77Phe) in the EC1 domain [21]. The polysyndactyly, broad thumb and cutaneous syndactyly overlap with Elsahy-Waters syndrome, which extends the TBHS2 phenotype towards the recessive form [21]. The sources consulted do not describe the course in adulthood, fertility or life expectancy, and the number of patients is too small to estimate organ-specific risks; the proportions in the following table are frequencies in a case series and not population risks.

Source: Li and colleagues, table 1; the literature column excludes patients with a SPECC1L variant and the family reclassified as Baraitser-Winter syndrome due to an ACTG1 variant, and the SPECC1L column excludes the patient with oblique facial cleft [8]. The SPECC1L counts in this table differ slightly from those of Bhoj and colleagues in section 3.11 because of differences in denominators between the compilations [5, 8].

3.14 Elsahy-Waters syndrome, the allelic recessive form of CDH11

Elsahy-Waters syndrome (branchioskeletogenital syndrome) combines moderate intellectual disability, craniofacial dysmorphism (brachycephaly, facial asymmetry, marked hypertelorism, blepharochalasis, proptosis, broad nose with concave dorsum and bulbous tip, midface hypoplasia, bifid uvula or partial cleft palate, and prognathism), progressive dental anomalies (dentigerous cysts, radicular dentin dysplasia and early tooth loss), vertebral fusions, mainly of C2–C3, and hypospadias; hearing loss is an additional manifestation [9]. Harms and colleagues confirmed in 2018 the biallelic cause in a boy and a girl with homozygous truncating variants and added upper eyelid coloboma as a rare manifestation [12]. Taskiran and colleagues described two Turkish sisters, born to consanguineous parents, with megalocornea, glaucoma, cataract and phthisis bulbi in the younger one, partial cutaneous syndactyly of the second and third toes, a dentigerous cyst and mild to borderline intellectual disability [52]. Castori and colleagues found a homozygous nonsense variant in the first exon in two Italian siblings [53]. Minatogawa and colleagues described in 2021 the first patient from East Asia, a Japanese man with a homozygous splicing variant, atlantoaxial instability due to posterior displacement of the odontoid process, thoracic fusion, a butterfly vertebra, sacralisation of L5 and multiple perineural cysts, and at that time counted six patients with molecular confirmation [54]. Orphanet records seven published cases and a prevalence of less than 1 per 1,000,000 [9]. In the comparison by Li and colleagues, global delay is constant in the recessive form and axial skeletal changes are frequent, whereas heart disease and umbilical defects were seen only in TBHS2, although the number of patients with the recessive form is small [8].

4. Clinical Recognition and Warning Signs

4.1 Prenatal period

Ultrasound may show hypertelorism, cleft lip, heart disease, pyelectasis and hypospadias, but the facial and genital signs are subtle and not very specific, and MID1 testing is not part of routine practice without a targeted suspicion [18]. The first ultrasound diagnosis, published in 1989, was made at 19 weeks by demonstrating hypertelorism and hypospadias in a fetus from a family with affected members in three generations; Spinelli and colleagues also cite an enlarged cisterna magna [3, 18]. A family history of boys with hypertelorism, hypospadias, clefts or neonatal deaths from aspiration, in the maternal line, is the element that guides the diagnosis when ultrasound shows a combination of midline anomalies [3, 18]. In SPECC1L-related syndrome, diaphragmatic hernia and omphalocele are the most characteristic prenatal findings [5, 58].

4.2 Newborn and infant

GeneReviews recommends suspecting MID1-OS in a boy with hypertelorism or telecanthus (present in practically all), hypospadias, laryngotracheo-oesophageal anomalies (especially laryngeal cleft) with swallowing difficulties and respiratory dysfunction, cleft lip and/or palate, developmental delay, congenital heart disease (VSD, ASD, persistent left superior vena cava, patent ductus arteriosus) and imperforate or ectopic anus; imaging may reveal vesicoureteral reflux, hydronephrosis and midline brain defects [1]. A family history compatible with X-linked inheritance (no father-to-son transmission) supports the diagnosis, but its absence does not exclude it [1]. In the hypospadias clinic, the Oxford Desk Reference advises looking for hypertelorism and laryngeal and swallowing problems as clues to Opitz G/BBB, and, in the hypertelorism clinic, asking about swallowing difficulties and looking for a widow's peak and hypospadias [29, 60]. In anorectal anomalies, associated hypertelorism likewise points to this syndrome [61].

4.3 Warning signs and emergencies

The emergency sign is the combination of choking during feeds, recurrent aspiration, stridor, wheezing, a weak, hoarse cry or recurrent pneumonia in an infant with hypertelorism and hypospadias: Smith describes it as suggestive of a potentially lethal laryngo-oesophageal defect, and the Oxford Desk Reference recommends considering laryngoscopy in infants with Opitz G/BBB [6, 29]. GeneReviews indicates laryngoscopy and chest radiography in those with choking during feeding, recurrent pneumonia or aspiration [1]. The absence of obvious choking does not exclude a mild laryngeal cleft, because in some infants the disorder is only functional and resolves [1]. Heart disease with signs of heart failure in the neonatal period is the other reason for urgency, as shown by the newborn described by Spinelli and colleagues, who died at 24 hours [18].

4.4 Child, adolescent and adult

At later ages, the diagnosis arises in the assessment of facial dysmorphism with hypertelorism, a repaired orofacial cleft, repaired hypospadias and learning difficulties; the Oxford Desk Reference notes that families with Opitz G/BBB are usually referred for a dysmorphology opinion and not because of a family history of intellectual disability [62]. The mother of an affected boy should be examined for hypertelorism, because this may be the only sign of heterozygosity [1, 11]. In an adult, the syndrome may be recognised in the context of heart disease with a suggestive facies, as in the Chinese case of heart failure [42]. In SPECC1L-related syndrome, Wild and colleagues recommend considering the diagnosis in any patient with diaphragmatic hernia who also has hypertelorism, a prominent forehead, a broad nasal root, anteverted nares, cleft lip and/or palate, branchial fistulas, omphalocele or bicornuate uterus [58]. In Teebi hypertelorism syndrome type 2, the signs that raise suspicion are the Teebi facies with a depressed nasal root, especially when associated with hypospadias, heart disease, an umbilical defect, broad thumbs or syndactyly, and when testing of MID1 and SPECC1L is negative [8, 21]. There is no newborn screening for any of these entities.

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

There are no validated formal clinical criteria [35]. GeneReviews defines the diagnosis of MID1-OS in a boy with suggestive findings and a hemizygous pathogenic or likely pathogenic variant in MID1; in a woman, the heterozygous variant is usually accompanied by isolated hypertelorism and only rarely by other manifestations [1]. According to the ACMG and Association for Molecular Pathology (AMP) standards, pathogenic and likely pathogenic variants have the same clinical value, and a variant of uncertain significance (VUS) neither confirms nor excludes the diagnosis [1]. For SPECC1L-related syndrome, the diagnosis is molecular and the reference phenotype is that described by Bhoj and colleagues [5].

5.2 Molecular tests

GeneReviews proposes two approaches. In the first, gene-targeted approach, MID1 is sequenced to detect missense, nonsense, splicing variants and small deletions and insertions; if negative, targeted deletion and duplication analysis follows (quantitative PCR, long-range PCR, MLPA or targeted microarray), because deletions of one or more exons or of the whole gene may escape sequencing [1]. Alternatively, a multigene panel including MID1 and the genes of the differential diagnosis is used, which limits VUS and findings in genes unrelated to the phenotype, bearing in mind that content and sensitivity vary between laboratories [1]. In the second approach, for atypical phenotypes, exome or genome sequencing is performed, whose detection of deletions and duplications by read depth may be lower than that of targeted analysis [1]. When an autosomal form is suspected, chromosomal microarray identifies the 22q11.2 deletion and copy number variants; the six probands with a MID1 variant in the series of Kruszka and colleagues all had a normal microarray [31]. SPECC1L should be included in panels for orofacial clefts, hypertelorism and diaphragmatic hernia, and the exon 3 deletion described in 2025 shows that copy number analysis is also necessary here [23, 58].

The MID1 proportions derive from the professional HGMD database and describe the distribution of known variant types, not the clinical sensitivity of the test [1].

5.3 Test yield and limitations

The yield of MID1 testing in patients with a clinical diagnosis of Opitz syndrome is low: De Falco and colleagues found variants in 11 of 63 referred boys (17%), Kruszka and colleagues in 6 of 25 families (24%), and Li and colleagues estimate that fewer than half of X-linked clinical cases have an identified MID1 variant [31, 33, 37]. A negative test therefore excludes neither the clinical diagnosis nor X-linked inheritance. Conversely, screening of SPECC1L in sporadic patients with Opitz syndrome defined by hypospadias and laryngotracheo-oesophageal defects and normal MID1 found no pathogenic variants, and the missense variants detected were already listed in population databases, outside the two domains in which the causal variants cluster [50]. In the Kruszka series, only 1 of the 19 probands without a MID1 variant had a SPECC1L variant [31]. Intronic variants are a source of VUS: because MID1 is not expressed in blood, mRNA analysis from peripheral blood is of little use, and minigene assays allowed three splicing variants to be reclassified [41]. Small intragenic duplications, such as the 57 kb duplication of exon 2, have been detected by molecular karyotyping in an infant with a minimal phenotype [39]. Maternal somatic or germline mosaicism is possible and is not excluded in an isolated boy whose mother tests negative in leucocytes [1].

5.4 Report content and interpretation

The report should state the gene, the transcript with version (NM_000381.4 for MID1; NM_015330.6 for SPECC1L), the variant in HGVS nomenclature, the zygosity (hemizygous in a boy, heterozygous in a woman), the ACMG/AMP classification and the evidence used, including segregation and functional studies [1, 10, 41]. Interpretation of new missense variants requires caution: the p.(Val534Leu) variant, inherited from an unaffected mother and present in a normal sister, was classified by the authors only as “possibly damaging” by one predictor, and the patient's phenotype (narial hypoplasia, preaxial polydactyly, hemispheric asymmetry) does not match the classic pattern [44]. The GeneReviews author offers to review MID1 VUS [1]. Family segregation is a useful argument: in the Perea-Cabrera case, heterozygosity in the mother and sisters and hemizygosity in the two affected brothers supported the PP4 criterion and classification as likely pathogenic [35].

5.5 Investigations after diagnosis

The initial assessment recommended by GeneReviews includes examination with attention to the palate, heart, genitourinary tract and lower airways; laryngoscopy and chest radiography if there is choking, recurrent pneumonia or aspiration; echocardiography; urinary tract ultrasound in boys with severe hypospadias; assessment of the position and patency of the anus; developmental assessment; audiological assessment in patients with a cleft; dental assessment; and a full ophthalmological examination with acuity, refraction and ocular alignment [1]. GeneGuidance adds a contrast swallow study and formal feeding assessment as a complement to laryngoscopy, and brain magnetic resonance imaging for defects of the corpus callosum and vermis [11]. In SPECC1L-related syndrome, Bhoj and colleagues recommend taking aortic root dilatation and craniosynostosis into account in management [22].

5.6 Prenatal and preimplantation diagnosis

When the familial MID1 variant is known, prenatal diagnosis and preimplantation genetic testing are possible [1]. The first molecular prenatal diagnosis was made in a Korean family that already had an affected son, with the variant c.1798insC in exon 13 (published designation, without a reference transcript) identified by chorionic villus sampling and amniocentesis in two pregnancies, and another case was diagnosed by array comparative genomic hybridisation (aCGH) in a fetus with heart disease and a 48 kb deletion at Xp22.2 encompassing the 3' untranslated region of MID1, according to the review by Spinelli and colleagues [18]. Without a known familial variant, a normal karyotype and aCGH do not exclude the syndrome [18].

5.7 Diagnostic algorithm

5.8 Diagnosis of Teebi hypertelorism syndrome type 2

There are no formal clinical criteria for TBHS2, and the diagnosis rests on the identification of a heterozygous pathogenic or likely pathogenic missense variant in CDH11 in a patient with Teebi facies [7, 8]. All published diagnoses were made by exome sequencing, and CDH11 should be included in panels for craniofacial dysmorphology, hypertelorism and syndromic hypospadias; a panel restricted to MID1 and SPECC1L will not detect it [8, 21]. Li and colleagues recommend sequencing SPECC1L and CDH11 in patients with a clinical diagnosis of Teebi syndrome still without a molecular cause [8]. The known variants are concentrated in domains EC1 to EC3 and in the calcium-binding regions, and no functional assay is available in clinical practice: the published adhesion and migration assays are research tools [8]. Classification of a new missense variant relies on absence from population databases, conservation of the residue, location in an intolerant domain (the MetaDome analysis in the original article identifies the EC1 and EC2 domains and their linkers as the most intolerant regions) and, above all, de novo occurrence or family segregation [8]. The report should distinguish a heterozygous missense variant, compatible with TBHS2, from biallelic truncating variants, compatible with Elsahy-Waters syndrome; an isolated heterozygous truncating variant in a patient with Teebi facies has no established significance in the sources consulted [8, 12]. After diagnosis, the assessments recommended by the original series and by the described phenotype are echocardiography, examination of the abdominal wall, genital examination in boys, ophthalmological assessment (strabismus, ptosis, eyelid coloboma), assessment of the palate and dentition, and developmental assessment [8, 21]. When the familial variant is known, prenatal diagnosis and preimplantation genetic diagnosis are technically possible, as in other monogenic disorders.

6. Differential Diagnosis

6.1 Comparative table

AD, autosomal dominant; AR, autosomal recessive; ID, intellectual disability.

6.2 X-linked Opitz syndrome, 22q11.2 deletion and SPECC1L

The most relevant differential lies within the class itself. Without molecular testing, it is difficult to distinguish the X-linked form from the 22q11.2 deletion form in a boy without a family history, because all the manifestations, except anteverted nares and posterior laryngeal clefts, occur in both [6, 60]. The distinction has practical consequences: the recurrence risk and the relatives at risk are different, and the 22q11.2 deletion requires its own immunological, endocrine and psychiatric assessment [1, 11]. SPECC1L-related syndrome is distinguished from MID1-related Opitz syndrome by the absence of hypospadias (0 of 14 boys), laryngeal cleft (0 of 29) and anorectal malformations (0 of 31), and by the presence of omphalocele, diaphragmatic hernia, ear pits and bicornuate uterus, differences that were statistically significant in the comparison by Bhoj and colleagues [5]. GeneReviews stresses that the absence of hypospadias argues against MID1 [1, 11]. Father-to-son transmission excludes X-linked inheritance and points to SPECC1L or the 22q11.2 deletion [5, 6].

6.3 Teebi syndrome and other causes of hypertelorism

The Oxford Desk Reference groups Teebi syndrome with the frontonasal dysplasias and notes that some cases are caused by SPECC1L [29]. Bhoj and colleagues reviewed 19 individuals from nine publications from 1987 to 2006 with a clinical diagnosis of Teebi syndrome without molecular testing: four reports, in addition to the original, fit the SPECC1L spectrum, two most likely correspond to Baraitser-Winter syndrome and three to unclassifiable hypertelorism syndromes [5]. A 937 kb duplication at Xq13 that includes EFNB1 was described in three women from three generations with marked hypertelorism and nail ridging as “X-linked Teebi syndrome” [5]. Baraitser-Winter syndrome shares hypertelorism, a ridged metopic suture, ptosis and a short, broad nose, and some patients with a SPECC1L variant had initially been diagnosed with Baraitser-Winter syndrome; intellectual disability (42 of 42), pachygyria and muscle problems are characteristic of the latter [5].

The differential within the Teebi group rests on the nose and the organs involved. In the compilation by Li and colleagues, the nasal root was broad or high in all patients with a SPECC1L variant and depressed in 68% of patients with a CDH11 variant; it was also depressed in 8 of 13 patients from the literature with a clinical diagnosis of Teebi syndrome, including those of the original family, which leaves open the molecular cause of some of these historical cases [8]. Craniosynostosis and diaphragmatic hernia point to SPECC1L, hypospadias is present in half of the boys with TBHS2 and absent in boys with a SPECC1L variant, and laryngeal cleft and anal anomalies have not been described in either form of Teebi syndrome [5, 8]. In a boy with hypertelorism and hypospadias, MID1 remains the first gene to study, but the presence of a depressed nasal root, broad thumbs, syndactyly or an umbilical defect without dysphagia or a laryngeal defect should lead to CDH11 being included in the panel [1, 8, 21]. Elsahy-Waters syndrome is distinguished by recessive inheritance with frequent consanguinity, constant intellectual disability, cervical vertebral fusions, radicular dentin dysplasia with early tooth loss and the reported absence of heart disease [8, 9, 54].

6.4 Namesakes not to be confused

Several entities share the Opitz eponym without any relationship to MID1: Smith-Lemli-Opitz syndrome (a defect of cholesterol synthesis due to biallelic DHCR7 variants), FG or Opitz-Kaveggia syndrome (MED12) and Bohring-Opitz syndrome (ASXL1, autosomal dominant, ORPHA:97297) [11, 62]. The work-up of anorectal anomalies adds STAR syndrome (FAM58A, X-linked dominant) and Townes-Brocks syndrome [61].

7. Treatments and Risk Management Strategies

7.1 General principles and level of evidence

There is no disease-modifying therapy for any of the entities in this class [1, 11]. Management is surgical, supportive and multidisciplinary, coordinated by a team that includes a craniofacial surgeon, ophthalmologist, paediatrician, paediatric urologist, cardiologist, pulmonologist, speech and language therapist and clinical geneticist [1]. The available guidance is that of the GeneReviews chapter, which has no section on published guidelines; no consensus statement or randomised trial on any intervention in this syndrome has been identified, and the underlying evidence consists of case reports and small series, totalling about 90 individuals with a MID1 variant [1, 11]. For SPECC1L-related syndrome, the evidence is limited to case series [11]. Recommendations from general guidelines (for example, on hypospadias) apply to the malformations, with the adaptations required by the syndromic context.

7.2 Airway, swallowing and laryngotracheo-oesophageal defects

Clinically significant laryngotracheo-oesophageal defects are treated surgically; tracheostomy is often needed in the initial phase to secure an adequate airway, and pharmacological antireflux therapy reduces the risk of aspiration until laryngeal competence is ensured [1]. Smith adds protection of the lungs by gastrostomy or jejunostomy, without which mortality from severe defects is high [6]. Tracheo-oesophageal fistula is cured by surgical division, but neither radiology nor bronchoscopy is infallible in diagnosis [63]. In non-syndromic type 1 laryngeal clefts, a series of six children from a tertiary centre (five boys; 6 months to 4 years) was initially treated with direct laryngobronchoscopy and interarytenoid injection of hyaluronic acid (1 to 3 mL), with or without supraglottoplasty; there was recurrence in three at 2–3 months, resolved by endoscopic laser repair, which the authors consider the reference treatment for type 1 [64]. This series does not include patients with Opitz G/BBB and serves only as technical context; the type of cleft (Benjamin-Inglis and Evans classification) determines the approach [64]. Antireflux medication, whose class and dosage GeneReviews does not specify, is that in usual paediatric use [1].

7.3 Orofacial clefts, hearing, speech and teeth

Cleft lip and/or palate and the other craniofacial anomalies are treated surgically by the craniofacial team, with speech and language therapy for secondary disorders, treatment of hearing loss, including tympanostomy tubes (pressure equalisation tubes) for recurrent otitis, and dental treatment of hypodontia [1]. The Brazilian study by Cassab and colleagues, with 14 men who had undergone cleft palate repair, found hearing loss in 2 and signs of central auditory pathway involvement, which reinforces the importance of audiological assessment beyond tympanometry [57].

7.4 Hypospadias and urinary tract

GeneReviews recommends surgical correction of hypospadias as needed and urological follow-up in significant cases [1]. The paediatric urology guidelines of the European Association of Urology and the European Society for Paediatric Urology (EAU/ESPU), in the edition presented in London in 2026, apply to the repair [65].

There is a relevant divergence regarding imaging. The EAU/ESPU panel, given contradictory data on associated urinary anomalies in unrecognised syndromes, does not recommend routine imaging in hypospadias [65]. GeneReviews recommends ultrasound to assess urinary dysfunction in boys with MID1-OS and severe hypospadias, because in this syndrome severe hypospadias is associated with vesicoureteral reflux and hydronephrosis [1]. The GeneReviews recommendation is the one applicable to a patient with a diagnosis of Opitz G/BBB, and the EAU/ESPU recommendation to isolated hypospadias. The European guideline also describes glans dehiscence in 9–17% and, in preputial reconstruction, dehiscence in 7–17% and secondary phimosis in 1.5%, and indicates caudal and penile blocks as equivalent analgesic options [65].

7.5 Heart, anus, eyes and development

Congenital heart defects are repaired surgically according to the usual indications, imperforate anus is corrected surgically, and ophthalmological abnormalities are treated with strabismus surgery and/or optical correction [1]. Neuropsychological and educational support is needed, and many boys with MID1-OS require special educational programmes [1]. Family support includes community resources, social services, home nursing and, when needed, palliative or respite care [1]. In adult heart failure, the case of Wang and colleagues was treated with standard therapy (vericiguat, dapagliflozin and bisoprolol), with no syndrome-specific feature described [42].

7.6 SPECC1L-related syndrome

Management is surgical and supportive for each malformation: orofacial clefts, umbilical and inguinal hernias, omphalocele, congenital diaphragmatic hernia and craniosynostosis [5, 11]. Bhoj and colleagues recommend including aortic root dilatation and craniosynostosis in management, and Kruszka and colleagues described critical aortic stenosis with post-stenotic root dilatation [22, 31]. The sources consulted do not define aortic intervention thresholds specific to this syndrome. The uterine anomalies found in all women assessed have reproductive implications that the sources do not quantify [5].

7.7 Anaesthesia and the perioperative period

There is no anaesthetic literature specific to MID1-related Opitz syndrome in the sources consulted; the implications derive from the malformations described by GeneReviews: laryngeal cleft, frequent tracheostomy in the initial phase, risk of aspiration and reflux, and heart disease [1]. For SPECC1L-related syndrome, Abdelhady and Tobias published in 2026 the first anaesthesia report, in a 4-year-old child undergoing thoracic laminectomy, and systematised the precautions [59].

Source: Abdelhady and Tobias [59]. In the case described, intubation with a 5.0 mm cuffed tube was easy (grade 1 glottic view) despite the micrognathia, there was postoperative desaturation to 80–85% corrected with oxygen at 2 L/min, and the child was discharged on the fourth day [59].

7.8 Pregnancy, delivery and the neonatal period

In the pregnancy of a fetus with suspected X-linked Opitz syndrome, the case of Spinelli and colleagues illustrates the need for delivery in a centre with neonatal intensive care and cardiac surgery, and in the case described antenatal corticosteroids were given because of the risk of preterm delivery [18]. In pregnancies of women with SPECC1L-related syndrome and bicornuate uterus, Bhoj and colleagues describe affected fetuses with severe diaphragmatic hernia [5]. The sources consulted contain no data on the obstetric course of women with bicornuate uterus or on lactation.

7.9 Regulatory status, clinical trials and developments

None of these developments changes clinical practice; no regulatory applications, opinions or authorisations relating to these diseases were found. A search without results does not demonstrate the absence of unregistered studies.

7.10 Transition to adulthood

Transition should include the long-term urological follow-up provided for by the EAU/ESPU for patients who have undergone hypospadias repair, cardiological reassessment of patients with heart disease, educational and vocational support and reproductive counselling [1, 65]. GeneReviews recommends offering genetic counselling to young adults who are affected, heterozygous or at risk of being heterozygous [1]. The authors of the heart failure case advocate longer follow-up of adults to characterise the long-term course [42].

7.11 Teebi hypertelorism syndrome type 2 and Elsahy-Waters syndrome

There is no targeted treatment or guideline for either of the CDH11 disorders, and no clinical trials are registered on ClinicalTrials.gov (search of 1 November 2026 for CDH11, Teebi and Elsahy-Waters), and cadherin-11 is not the target of any gene or molecular therapy in development for these syndromes in the sources consulted [11, 68]. Management is symptomatic and anticipatory, directed at the manifestations present: craniofacial and oculoplastic assessment of hypertelorism, proptosis, ptosis and eyelid coloboma; ophthalmology for strabismus and refractive error; cleft palate surgery with speech and hearing follow-up; paediatric urology for hypospadias, according to the general principles in section 7.4; cardiology for congenital heart defects; paediatric surgery for umbilical defects; and early intervention, speech and language therapy and educational support when there is delay [8, 11, 21]. In TBHS2, the absence of craniosynostosis and diaphragmatic hernia in the original series does not remove the need for clinical examination, because the series has only 19 patients [8]. In Elsahy-Waters syndrome, specialised dental follow-up (dentigerous cysts, radicular dysplasia, early tooth loss), ophthalmological follow-up (glaucoma, cataract and megalocornea described) and cervical spine follow-up are added; the atlantoaxial instability described in a Japanese patient justifies assessing the cervical spine before anaesthesia or cervical manipulation, by analogy with other dysplasias with cervical fusions [9, 52, 54]. The sources consulted do not describe anaesthetic difficulties specific to TBHS2; the 2026 perioperative report on Teebi syndrome concerns a patient with a SPECC1L variant [59].

8. Reproductive Options and Family Counselling

8.1 MID1-related Opitz G/BBB: risks by scenario

MID1-OS is inherited in an X-linked manner [1]. The father of an affected boy does not have the disease or the variant and does not need to be tested [1]. When there is more than one affected individual in the family, the mother is an obligate heterozygote; if a woman has more than one affected son, no other affected relative and a variant not detectable in leucocyte DNA, the most likely explanation is germline mosaicism [1]. In a boy without other affected relatives (simplex case), the mother may be heterozygous, the variant may have arisen de novo in the proband, or the mother may have somatic or germline mosaicism; de novo variants have been described in several boys, including one of the Portuguese patients of Maia and colleagues, and GeneReviews recommends testing the mother to estimate the recurrence risk [1, 45].

8.2 Carrier testing and counselling of minors

Detection of heterozygous women among at-risk relatives requires that the familial variant has been identified [1]. Since most heterozygous women have only hypertelorism and some not even that, clinical examination is not sufficient to exclude carrier status: in the Mexican family of Perea-Cabrera, the heterozygous mother and sisters had no dysmorphism, and in the Italian family of Spinelli the heterozygous mother and aunt did not either [18, 35]. Risk determination and discussion of reproductive options should ideally precede pregnancy, and counselling should be offered to young adults who are affected, heterozygous or at risk [1]. The sources consulted do not specifically address carrier testing in minors.

8.3 Prenatal and preimplantation diagnosis

Once the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible; GeneReviews acknowledges that there are differing views, among professionals and families, on the use of prenatal diagnosis [1]. Intrafamilial variability makes it impossible to predict severity in a hemizygous male fetus, and detailed anomaly ultrasound and fetal echocardiography help to characterise the malformations [1, 18]. In the case of Spinelli and colleagues, the family chose to continue the pregnancy after multidisciplinary counselling [18].

8.4 SPECC1L-related syndrome and the 22q11.2 deletion form

SPECC1L-related syndrome is inherited in an autosomal dominant manner, with male-to-male transmission documented in Teebi's family and in others, and with de novo variants in five of the nine families in the series of Bhoj and colleagues [5]. Each child of a carrier has a 50% probability of inheriting the variant, with variable expressivity: in Bhoj's family 4, a woman with a de novo variant and mild manifestations had two fetuses with severe diaphragmatic hernia [5]. This variability justifies offering targeted ultrasound (diaphragm, abdominal wall, heart) in the pregnancies of carriers and prenatal or preimplantation diagnosis when the variant is known [5, 58]. The sources consulted do not describe parental mosaicism in this syndrome. In the 22q11.2 deletion form, the risk of transmission is 50% for the offspring of a carrier, and males and females are affected with equal frequency [6]. The Oxford Desk Reference recommends considering the unmasking of a recessive variant on the non-deleted allele when the phenotype of a child with a 22q11.2 deletion differs from that of the carrier parent, a mechanism proposed for an autosomal recessive form of Opitz G/BBB [69].

8.5 Importance of molecular distinction for counselling

A clinical diagnosis of “Opitz G/BBB” is not sufficient for counselling: in the X-linked form the risk depends on the mother's status and the sons of an affected man are not affected, whereas in the autosomal dominant forms the risk is 50% for the offspring of any carrier, regardless of sex [1, 5]. Bhoj and colleagues advocate nosological separation precisely because the medical and surgical complications of the two syndromes do not overlap and counselling differs [5]. The Mexican family of Perea-Cabrera illustrates the risk of error: consanguinity and the two affected brothers suggested autosomal recessive inheritance, until testing demonstrated X-linked inheritance [35].

8.6 Teebi hypertelorism syndrome type 2 and Elsahy-Waters syndrome

TBHS2 is autosomal dominant: each child of a carrier has a 50% probability of inheriting the variant, regardless of sex, and expressivity is variable within families, with some patients having normal development and others delay [7, 8]. Five of the nine families in the original series had de novo variants; when neither parent has the variant in blood, the recurrence risk for siblings is low but not zero, because of the possibility of germline mosaicism, which the sources consulted do not quantify for this gene [7, 8]. Since facial expression may be subtle, parental testing should be molecular and not merely clinical. Elsahy-Waters syndrome is autosomal recessive, with a 25% risk for each sibling of a patient when both parents are carriers, and with frequent parental consanguinity in the families described [11, 52]. Heterozygous carriers of a truncating variant have no described phenotype in the Elsahy-Waters families, which reinforces the mechanistic distinction between dominant missense variants and recessive truncating variants; counselling therefore depends on the variant class and not only on the gene [8, 52]. Prenatal diagnosis by amniocentesis or chorionic villus sampling and preimplantation genetic diagnosis are possible when the familial variants have been identified.

9. Special Considerations: Population Diversity and Epidemiology

9.1 Prevalence and incidence

Orphanet records the worldwide point prevalence of Opitz GBBB syndrome as unknown, with no validated estimate [2]. MedlinePlus Genetics states that the X-linked form affects 1 in 10,000 to 50,000 boys, probably with underdiagnosis, and Spinelli and colleagues cite 1 in 50,000 to 100,000 boys; neither estimate states a source population study, and they differ by a factor of two to ten [17, 18]. The available counts are of published cases and not of prevalence: about 90 individuals with a MID1 variant and a clinical synopsis up to 2023, and 184 X-linked cases with a confirmed variant in the compilation by Li and colleagues [1, 33]. An estimate for “Opitz G/BBB” in general would mix MID1, SPECC1L and the 22q11.2 deletion [11]. For SPECC1L-related syndrome, Orphanet assigns the class of less than 1/1,000,000 and records 25 cases or families, and Bhoj and colleagues brought together 31 patients from 12 families up to 2019 [4, 5].

9.2 Data by region

The series and reports come mainly from Europe and the United States: Italian groups assembled the largest series of MID1 variants and the functional splicing studies [37, 38, 40, 41], a French group studied the embryonic expression of the gene [70], and Philadelphia groups characterised SPECC1L-related syndrome in collaboration with centres in France, Denmark, Turkey, Mexico and Portugal [5, 31, 58]. In Portugal, Maia and colleagues, from Porto, described four patients from two families with new MID1 variants, one inherited from the mother and the other de novo, and carried out the genotype–phenotype analysis of 91 boys [45]. The Hospital Pediátrico de Coimbra was part of the European consortium that characterised SPECC1L-related syndrome [5]. In Brazil, the Hospital for Rehabilitation of Craniofacial Anomalies of the University of São Paulo, in Bauru, published the audiological study of 14 men with the syndrome, and the patient with oblique facial cleft and the SPECC1L p.(Gln415Pro) variant was of Brazilian origin [47, 57]. In Latin America, the Latin American Collaborative Study of Congenital Malformations (ECLAMC), with surveillance of 4,020,384 newborns in 159 centres in six countries between 1982 and 2011, found hypospadias in 11.3 per 10,000 and the association of hypospadias with craniofacial anomalies in 0.59 per 10,000, without identifying Opitz syndrome separately [71]. Patients from Mexico, China and Korea have also been described, and Teebi's original family was Arab [5, 18, 35, 42, 43]. No founder variants have been described.

TBHS2 has no estimated prevalence: Orphanet does not assign it a code of its own and associates CDH11 only with branchioskeletogenital syndrome (ORPHA:1299), and code ORPHA:1519 refers exclusively to the SPECC1L-related form [4, 9]. The 19 patients in the original series come from the United States, Canada, Italy, Spain, Belgium and Australia, and the only subsequent published case is Japanese; Elsahy-Waters syndrome has been described in Turkey, India, Saudi Arabia, Italy and Japan, with a prevalence of less than 1 per 1,000,000 according to Orphanet [8, 9, 12, 21, 52–54]. The sources consulted describe no patients from Portugal or Brazil with CDH11 variants, and no founder variants.

9.3 Gaps

There are no population-based studies, national registries or birth incidence data for any of these entities in the sources consulted, and the lack of data from Portugal and Brazil beyond those cited reflects only what these sources contain. Ascertainment bias towards severe forms and intrafamilial variability suggest that mild forms, especially in heterozygous women and in boys with isolated hypertelorism, are underdiagnosed [39, 46].

9.4 European reference networks and patient associations

The relevant European reference networks are ERN CRANIO, for craniofacial anomalies, orofacial clefts and rare ear, nose and throat disorders; ERN ITHACA, for rare congenital malformations and intellectual disability; ERNICA, for congenital digestive disorders, including oesophageal and anorectal malformations; and eUROGEN, for rare urogenital diseases [25–28]. GeneReviews lists as resources the American Cleft Palate-Craniofacial Association, Face Equality International (United Kingdom) and the MedlinePlus pages on the syndrome and on hypospadias repair [1, 17, 72, 73].

10. Illustrative Clinical Case

10.1 Prenatal diagnosis of maternally inherited X-linked Opitz G/BBB

Spinelli and colleagues, from Naples and Rome, published in 2015 the case of a 28-year-old nulliparous woman referred at 19 weeks of gestation for suspected fetal heart disease, after normal first-trimester screening and a nuchal translucency of 1.4 mm [18]. Ultrasound showed a male fetus with complex congenital heart disease, consisting of a perimembranous VSD, an ostium primum ASD or partial atrioventricular canal and a persistent left superior vena cava, associated with bilateral cleft lip, mild hypertelorism and bilateral pyelectasis [18]. Amniocentesis at 20 weeks, with karyotype and 44K aCGH, was normal [18]. Genetic counselling revealed that a 1-year-old maternal nephew had hypertelorism, hypospadias and an ASD and VSD that resolved spontaneously; the family history and ultrasound led to suspicion of an X-linked midline disorder, and the parents decided to continue the pregnancy after multidisciplinary counselling [18]. At 28 weeks, ultrasound confirmed the bilateral cleft lip, mild hypertelorism and pyelectasis, and added cortical hyperechogenicity of the right kidney with upper-pole caliectasis, hypospadias, agenesis of the ductus venosus with anomalous umbilical vein drainage, worsening cardiac function and cardiomegaly; antenatal corticosteroids were given and delivery was planned at a centre with neonatal intensive care and cardiac surgery [18].

At 30 weeks, spontaneous, dystocic preterm labour led to caesarean section. The male newborn weighed 1,254 g (34th centile), with Apgar scores of 5 at the first minute and 6 at the fifth, and had hypertelorism, cleft lip and palate, hypospadias, crossed fused renal ectopia, severe heart disease and imperforate anus [18]. Sequencing of MID1 identified the variant NM_000381.4:c.1285+1G>T (p.?), previously associated with the syndrome and known to alter splicing of exon 5 [10, 18, 41]. The newborn died at 24 hours of heart failure, and the parents declined autopsy [18]. The mother and her sister were heterozygous for the same variant, without evident signs of the syndrome; the nephew and the maternal grandmother were not tested [18].

The figures of the article, which is open access, show the fetal cardiac anomalies at 19 and 28 weeks (https://pmc.ncbi.nlm.nih.gov/articles/PMC4434197/figure/fig1/), the bilateral cleft lip on two-dimensional and three-dimensional ultrasound (https://pmc.ncbi.nlm.nih.gov/articles/PMC4434197/figure/fig2/), the facies of the newborn with a broad nasal root, hypertelorism and bilateral cleft lip and palate (https://pmc.ncbi.nlm.nih.gov/articles/PMC4434197/figure/fig3/) and the pedigree (https://pmc.ncbi.nlm.nih.gov/articles/PMC4434197/figure/fig4/) [18].

10.2 Lessons from the case

The case brings together the elements that define the syndrome and the limitations of prenatal diagnosis: facial and genital anomalies are subtle on ultrasound, a normal aCGH does not exclude a monogenic disorder, and it was the family history, with a maternal nephew with hypertelorism and hypospadias, that guided testing [18]. It also shows intrafamilial variability, from the neonatally lethal form in the fetus to the heterozygous women without signs and the nephew with spontaneously resolving heart disease, and the severity that complex heart disease can confer, heart disease being described in about a quarter of boys [1, 18]. The management described reflects the choices of one family and one centre and does not constitute a routine protocol.

10.3 Complementary case: SPECC1L-related syndrome

In family 4 of Bhoj and colleagues, a woman born at term had at birth hypertelorism, a natal tooth, ASD and umbilical hernia, with normal development; in adulthood she had short stature, short limbs, fingers and toes, arched eyebrows, a high, broad nasal root, anteverted nares, a long philtrum, operated micrognathia and bicornuate uterus [5]. In her first pregnancy, the 20-week ultrasound showed a female fetus with severe diaphragmatic hernia, and the pregnancy was terminated at 22 weeks; autopsy revealed hypertelorism, a left posterior diaphragmatic hernia with spleen, pancreas, stomach and left hepatic lobe in the chest, and pulmonary hypoplasia, markedly enlarged ovaries and bicornuate uterus [5]. Before the diagnosis had been completed, there was a new pregnancy: at 15 weeks and 6 days, another female fetus with severe diaphragmatic hernia and “lemon” and “banana” cranial signs, terminated at 17 weeks and 3 days; autopsy showed complete absence of the left hemidiaphragm, a muscular VSD, enlarged ovaries and bicornuate uterus, without dysraphism [5]. The mother's de novo variant NM_015330.6:c.1258G>A p.(Glu420Lys) was present in both fetuses and absent in a healthy brother [5, 10]. The case shows how a mildly affected woman can have offspring with lethal malformations and the importance of molecular diagnosis before a further pregnancy [5].

10.4 Complementary case: Teebi hypertelorism syndrome type 2

Kuroda and colleagues, from the Kanagawa Children's Medical Center, described in 2024 a Japanese boy seen at 10 months with normal developmental milestones, hypertelorism, strabismus, hypospadias and shawl scrotum [21]. In the hands there were broad thumbs, with a bifid right thumb on radiography, polysyndactyly of the left fourth finger and cutaneous syndactyly of the left third and fourth fingers [21]. Exome sequencing identified the de novo variant NM_001797.4:c.229C>T p.(Leu77Phe) in the EC1 domain, at a residue lining the hydrophobic pocket into which the side chains of the partner cadherin-11 insert during trans dimerisation [10, 21]. The authors considered the picture compatible with TBHS2, but noted that polysyndactyly, a broad thumb and cutaneous syndactyly are characteristic of Elsahy-Waters syndrome, and proposed that the two syndromes form a spectrum [21]. The case shows that hypospadias with hypertelorism is not exclusive to MID1 and that CDH11 should be part of the investigation of a boy with this phenotype and normal MID1.

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

The vital prognosis of MID1-related Opitz G/BBB depends mainly on the severity of the laryngotracheo-oesophageal defect and the heart disease: mortality is high in severe laryngo-oesophageal defects without repair and without pulmonary protection, whereas survivors, after initial poor weight gain, grow normally [6]. Functional forms of dysphagia improve with age and disappear in early childhood [1]. The neurological prognosis is variable: about 30% of boys have developmental delay or intellectual disability, partly secondary to surgery, and many require special education [1]. The sources consulted provide no data on long-term survival, quality of life or male fertility; adult data are limited to isolated reports of heart failure, a urothelial tumour and benign pituitary and bone tumours in a heterozygous woman [3, 42, 56]. In SPECC1L-related syndrome, severity is determined by diaphragmatic hernia, omphalocele and any aortic dilatation; most patients described have normal intelligence, with intellectual disability in 3 of 23 after 2 years of age, and mean adult height is 1.56 standard deviations below the mean [5, 58].

In Teebi hypertelorism syndrome type 2, the original series describes normal development in 12 of 19 patients and delay, mostly mild and limited to language, in seven, and the families with vertical transmission include carriers who have had children, but there are no data on survival, function in adulthood or late complications [8]. In Elsahy-Waters syndrome, intellectual disability is constant and the dental and vertebral complications are progressive, with early tooth loss and, in one patient, atlantoaxial instability in adulthood [9, 54].

11.2 Surveillance

The sources do not define fixed intervals for most assessments, which depend on the malformations present; the only explicit interval in GeneReviews is the annual one for audiology [1].

12. Summary and Final Considerations

Opitz G/BBB syndrome is now understood as an X-linked midline malformation syndrome caused by loss of function of MID1, a microtubule-associated ubiquitin ligase that regulates phosphatase 2A during development of the face, larynx, oesophagus, heart, genital tubercle, anus and midline brain structures [1, 3]. Boys almost always have hypertelorism and, in most cases, hypospadias, and the manifestation that determines survival is the laryngotracheo-oesophageal defect, which should be sought by laryngoscopy in any infant with hypertelorism and hypospadias who chokes or has recurrent pneumonia [1, 6]. Heterozygous women usually have only hypertelorism, which makes examination of the mother useful but insufficient to exclude carrier status [1, 33]. The former autosomal dominant form has split into two entities: some patients had the 22q11.2 deletion, and the families linked to 22q11.2 without a deletion turned out to have SPECC1L variants, whose phenotype, without hypospadias or laryngeal cleft and with omphalocele, diaphragmatic hernia, bicornuate uterus and aortic dilatation, justifies the designation SPECC1L-related syndrome or Teebi syndrome [3, 5, 31]. MID1 testing has a yield of less than half in clinical diagnoses, and a negative result requires searching for deletions and duplications, the 22q11.2 deletion, SPECC1L and other genes by exome sequencing [1, 33, 37]. Treatment is surgical and multidisciplinary, with no targeted therapy or ongoing trials, and the quality of evidence is limited to case series and expert guidance [11, 66]. Molecular distinction between the entities is the basis of counselling, because the recurrence risks, the relatives at risk and the complications to be monitored differ [1, 5].

Teebi hypertelorism syndrome type 2, caused by heterozygous missense variants in the extracellular domains of CDH11, completes the class: it shares the Teebi facies, but has a depressed nasal root, hypospadias in half of boys, heart disease and umbilical defects in about a quarter of patients and normal development in most, without laryngeal cleft, craniosynostosis or diaphragmatic hernia [7, 8]. Biallelic truncating variants in the same gene cause Elsahy-Waters syndrome, which is recessive, with intellectual disability, vertebral fusions and dental dysplasia, making variant class and zygosity decisive for counselling [8, 9].

13. References

1. Meroni G. MID1-Related Opitz G/BBB Syndrome. 2004 Dec 17 [updated 2023 Oct 19]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1327/
2. Orphanet. Opitz GBBB syndrome (ORPHA:2745) [Internet]. Paris: INSERM; [updated 2026-06-23; accessed 2026-10-29]. Available from: https://www.orpha.net/en/disease/detail/2745
3. Online Mendelian Inheritance in Man, OMIM®. MIM Number: 300000: Opitz GBBB syndrome; GBBB [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026-10-29]. Available from: https://omim.org/entry/300000
4. Orphanet. SPECC1L-related hypertelorism syndrome (ORPHA:1519) [Internet]. Paris: INSERM; [updated 2026-06-23; accessed 2026-10-29]. Available from: https://www.orpha.net/en/disease/detail/1519
5. Bhoj EJ, Haye D, Toutain A, Bonneau D, Nielsen IK, Lund IB, et al. Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes. Eur J Med Genet. 2019;62(12):103588. doi:10.1016/j.ejmg.2018.11.022. PMID: 30472488. PMC6594898
6. Jones KL, Jones MC, del Campo M. Opitz G/BBB syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 170–3.
7. Online Mendelian Inheritance in Man, OMIM®. MIM Number: 619736: Teebi hypertelorism syndrome 2; TBHS2 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026-11-01]. Available from: https://omim.org/entry/619736
8. Li D, March ME, Fortugno P, Cox LL, Matsuoka LS, Monetta R, et al. Pathogenic variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome. Hum Genet. 2021;140(7):1061-76. doi:10.1007/s00439-021-02274-3. PMID: 33811546. PMC9245547
9. Orphanet. Branchioskeletogenital syndrome (ORPHA:1299) [Internet]. Paris: INSERM; [accessed 2026-11-01]. Available from: https://www.orpha.net/en/disease/detail/1299
10. VariantValidator [Internet]. Manchester: University of Manchester; [accessed 2026-10-29]. Available from: https://rest.variantvalidator.org
11. GeneGuidance. MID1, SPECC1L and CDH11 entries [database]. Version of 2026-09-26.
12. Harms FL, Nampoothiri S, Anazi S, Yesodharan D, Alawi M, Kutsche K, et al. Elsahy-Waters syndrome is caused by biallelic mutations in CDH11. Am J Med Genet A. 2018;176(2):477-82. doi:10.1002/ajmg.a.38568. PMID: 29271567.
13. Online Mendelian Inheritance in Man, OMIM®. MIM Number: 145420: Teebi hypertelorism syndrome 1; TBHS1 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026-10-29]. Available from: https://omim.org/entry/145420
14. Online Mendelian Inheritance in Man, OMIM®. MIM Number: 600251: Facial clefting, oblique, 1; OBLFC1 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026-10-29]. Available from: https://omim.org/entry/600251
15. McDonald-McGinn DM, Hain HS, Emanuel BS, Zackai EH. 22q11.2 Deletion Syndrome. 1999 Sep 23 [updated 2020 Feb 27; revised 2025 May 8]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 20301696. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1523/
16. Orphanet. 22q11.2 deletion syndrome (ORPHA:567) [Internet]. Paris: INSERM; accessed 2026 Oct 3. Available from: https://www.orpha.net/en/disease/detail/567
17. MedlinePlus Genetics. Opitz G/BBB syndrome [Internet]. Bethesda (MD): National Library of Medicine; [accessed 2026-10-29]. Available from: https://medlineplus.gov/genetics/condition/opitz-g-bbb-syndrome/
18. Spinelli M, Sica C, Dallapiccola B, Novelli A, Di Meglio L, Martinelli P. The Challenge of Prenatal Diagnostic Work-Up of Maternally Inherited X-Linked Opitz G/BBB: Case Report and Literature Review. Case Rep Obstet Gynecol. 2015;2015:830108. doi:10.1155/2015/830108. PMID: 26064728. PMC4434197
19. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. 22q11.2 microdeletion syndrome (velo-cardio-facial syndrome, DiGeorge syndrome, Shprintzen syndrome); p. 386–391.
20. Blagojevic C, Heung T, Theriault M, Tomita-Mitchell A, Chakraborty P, Kernohan K, et al. Estimate of the contemporary live-birth prevalence of recurrent 22q11.2 deletions: a cross-sectional analysis from population-based newborn screening. CMAJ Open. 2021;9(3):E802-E809. doi:10.9778/cmajo.20200294. PMID: 34404688.
21. Kuroda Y, Saito Y, Enomoto Y, Naruto T, Kurosawa K. A Japanese patient with Teebi hypertelorism syndrome and a novel CDH11 EC1 domain variant. Am J Med Genet A. 2024;194(1):94-99. doi:10.1002/ajmg.a.63386. PMID: 37646430.
22. Bhoj EJ, Li D, Harr MH, Tian L, Wang T, Zhao Y, et al. Expanding the SPECC1L mutation phenotypic spectrum to include Teebi hypertelorism syndrome. Am J Med Genet A. 2015;167A(11):2497-502. doi:10.1002/ajmg.a.37217. PMID: 26111080.
23. Babai A, Oliveira D, Gialeli A, Drozniewska M, Kainov Y, Dias C. Disruption of SPECC1L translation initiation by intragenic deletion: novel pathogenic mechanism in Teebi-hypertelorism syndrome. NPJ Genom Med. 2025;10(1):68. doi:10.1038/s41525-025-00513-4. PMID: 41120295. PMC12541090
24. Sumitomo Pharma America, Inc. RETHYMIC (allogeneic processed thymus tissue–agdc) implant. Prescribing information [Internet]. DailyMed, U.S. National Library of Medicine; version published 2025 Dec 29 (initial FDA approval 2021). Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e0022c28-8cda-4f1e-bcf1-1f440d37ec4a
25. ERN CRANIO – European Reference Network for rare craniofacial anomalies and ENT disorders [Internet]. [accessed 2026-10-29]. Available from: https://www.ern-cranio.eu
26. ERN ITHACA – European Reference Network on rare congenital malformations and rare intellectual disability [Internet]. [accessed 2026-10-29]. Available from: https://ern-ithaca.eu
27. ERNICA – European Reference Network on rare inherited and congenital digestive disorders [Internet]. [accessed 2026-10-29]. Available from: https://www.ern-ernica.eu
28. eUROGEN – European Reference Network for rare urogenital diseases and complex conditions [Internet]. [accessed 2026-10-29]. Available from: https://eurogen-ern.eu
29. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 258–9 (Ocular hypertelorism).
30. Quaderi NA, Schweiger S, Gaudenz K, Franco B, Rugarli EI, Berger W, et al. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat Genet. 1997;17(3):285-91. doi:10.1038/ng1197-285. PMID: 9354791.
31. Kruszka P, Li D, Harr MH, Wilson NR, Swarr D, McCormick EM, et al. Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G/BBB syndrome. J Med Genet. 2015;52(2):104-10. doi:10.1136/jmedgenet-2014-102677. PMID: 25412741. PMC4393015
32. Online Mendelian Inheritance in Man, OMIM®. MIM Number: 300552: Midline 1; MID1 [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026-10-29]. Available from: https://omim.org/entry/300552
33. Li B, Zhou T, Zou Y. Mid1/Mid2 expression in craniofacial development and a literature review of X-linked opitz syndrome. Mol Genet Genomic Med. 2016;4(1):95-105. doi:10.1002/mgg3.183. PMID: 26788540. PMC4707030
34. Mnayer L, Khuri S, Merheby HA, Meroni G, Elsas LJ. A structure-function study of MID1 mutations associated with a mild Opitz phenotype. Mol Genet Metab. 2006;87(3):198-203. doi:10.1016/j.ymgme.2005.10.014. PMID: 16378742.
35. Perea-Cabrera M, Granados-Riveron JT, Segura-Stanford B, Moreno-Vargas LM, Prada-Gracia D, Moran-Espinosa MC, et al. Opitz GBBB syndrome with total anomalous pulmonary venous connection: A new MID1 gene variant. Mol Genet Genomic Med. 2023;11(9):e2234. doi:10.1002/mgg3.2234. PMID: 37498300. PMC10496055
36. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 4–7 (Approach to the consultation).
37. De Falco F, Cainarca S, Andolfi G, Ferrentino R, Berti C, Rodríguez Criado G, et al. X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. Am J Med Genet A. 2003;120A(2):222-8. doi:10.1002/ajmg.a.10265. PMID: 12833403.
38. Fontanella B, Russolillo G, Meroni G. MID1 mutations in patients with X-linked Opitz G/BBB syndrome. Hum Mutat. 2008;29(5):584-94. doi:10.1002/humu.20706. PMID: 18360914.
39. Hüning I, Kutsche K, Rajaei S, Erlandsson A, Lovmar L, Rundberg J, et al. Exon 2 duplication of the MID1 gene in a patient with a mild phenotype of Opitz G/BBB syndrome. Eur J Med Genet. 2013;56(4):188-91. doi:10.1016/j.ejmg.2013.01.004. PMID: 23354372.
40. Migliore C, Athanasakis E, Dahoun S, Wonkam A, Lees M, Calabrese O, et al. Complex rearrangement of the exon 6 genomic region among Opitz G/BBB Syndrome MID1 alterations. Eur J Med Genet. 2013;56(8):404-10. doi:10.1016/j.ejmg.2013.05.009. PMID: 23791568.
41. Micale L, Russo F, Mascaro M, Morlino S, Nardella G, Fusco C, et al. Opitz syndrome: improving clinical interpretation of intronic variants in MID1 gene. Pediatr Res. 2023;93(5):1208-1215. doi:10.1038/s41390-022-02237-y. PMID: 35953512.
42. Wang Y, Wu X, Wang K. Heart failure caused by Opitz syndrome: a case report and literature review. BMC Cardiovasc Disord. 2025;25(1):857. doi:10.1186/s12872-025-05297-0. PMID: 41331794. PMC12673712
43. Yan Y, He L, Yang Y, Wang D, Zhang H, Chen Y. [Clinical feature and genetic analysis of a child with X-linked Opitz G/BBB syndrome caused by nonsense variant in the MID1 gene mediated by mRNA degradation escape]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2025;42(2):219-225. doi:10.3760/cma.j.cn511374-20240905-00470. PMID: 40350402.
44. Wu Q, Feng X, Yan Y, Yu B, Dai C, Wei J. A Novel MID1 Mutation Identified in a Patient With Craniofacial Anomalies and X-Linked Intellectual Disability. J Craniofac Surg. 2026:. doi:10.1097/SCS.0000000000012575. PMID: 41842826.
45. Maia N, Nabais Sá MJ, Tkachenko N, Soares G, Marques I, Rodrigues B, et al. Two Novel Pathogenic MID1 Variants and Genotype-Phenotype Correlation Reanalysis in X-Linked Opitz G/BBB Syndrome. Mol Syndromol. 2017;9(1):45-51. doi:10.1159/000479177. PMID: 29456483. PMC5803688
46. So J, Suckow V, Kijas Z, Kalscheuer V, Moser B, Winter J, et al. Mild phenotypes in a series of patients with Opitz GBBB syndrome with MID1 mutations. Am J Med Genet A. 2005;132A(1):1-7. doi:10.1002/ajmg.a.30407. PMID: 15558842.
47. Online Mendelian Inheritance in Man, OMIM®. MIM Number: 614140: Sperm antigen with calponin homology and coiled-coil domains 1-like; SPECC1L [Internet]. Baltimore (MD): Johns Hopkins University; [accessed 2026-10-29]. Available from: https://omim.org/entry/614140
48. Saadi I, Alkuraya FS, Gisselbrecht SS, Goessling W, Cavallesco R, Turbe-Doan A, et al. Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting. Am J Hum Genet. 2011;89(1):44-55. doi:10.1016/j.ajhg.2011.05.023. PMID: 21703590. PMC3135813
49. Wilson NR, Olm-Shipman AJ, Acevedo DS, Palaniyandi K, Hall EG, Kosa E, et al. SPECC1L deficiency results in increased adherens junction stability and reduced cranial neural crest cell delamination. Sci Rep. 2016;6:17735. doi:10.1038/srep17735. PMID: 26787558. PMC4726231
50. Migliore C, Vendramin A, McKee S, Prontera P, Faravelli F, Sachdev R, et al. SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome. Genes (Basel). 2022;13(2):252. doi:10.3390/genes13020252. PMID: 35205294. PMC8871657
51. Tran AJ, Hufft-Martinez BM, Thalman DN, Maili L, McKinney SA, Goering JP, et al. Loss of SPECC1L in cranial neural crest cells results in increased hedgehog signaling and frontonasal dysplasia. Front Physiol. 2026;17:1751758. doi:10.3389/fphys.2026.1751758. PMID: 41657552. PMC12873473
52. Taskiran EZ, Karaosmanoglu B, Koşukcu C, Doğan ÖA, Taylan-Şekeroğlu H, Şimşek-Kiper PÖ, et al. Homozygous indel mutation in CDH11 as the probable cause of Elsahy-Waters syndrome. Am J Med Genet A. 2017;173(12):3143-52. doi:10.1002/ajmg.a.38495. PMID: 28988429.
53. Castori M, Ott CE, Bisceglia L, Leone MP, Mazza T, Castellana S, et al. A novel mutation in CDH11, encoding cadherin-11, cause Branchioskeletogenital (Elsahy-Waters) syndrome. Am J Med Genet A. 2018;176(9):2028-33. doi:10.1002/ajmg.a.40379. PMID: 30194892.
54. Minatogawa M, Tsukahara Y, Yuzuriha S, Kosho T. Detailed clinical and radiological features of the first patient with Elsahy-Waters syndrome in East Asia. Am J Med Genet A. 2021;185(12):3909-15. doi:10.1002/ajmg.a.62423. PMID: 34278706.
55. Jones KL, Jones MC, del Campo M. Exstrophy of bladder sequence. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 886–7.
56. Williams JF, Santoscoy Gutierrez JF, Nolazco JI, Steele GS, Burk KS, Hirsch MS, et al. Clear Cell Adenocarcinoma of the Urinary Tract Arising in a Young Man With the Congenital Malformation Disorder Opitz Syndrome: A Case Report. Int J Surg Pathol. 2026;34(4):1074-1079. doi:10.1177/10668969251412914. PMID: 41574915.
57. Cassab TV, Zanchetta S, Giacheti CM, Zorzetto NL, Richieri-Costa A. Auditory findings and electrophysiologics in individuals with G/BBB syndrome. Braz J Otorhinolaryngol. 2011;77(6):768-74. doi:10.1590/S1808-86942011000600014. PMID: 22183284. PMC9443729
58. Wild KT, Gordon T, Bhoj EJ, Du H, Jhangiani SN, Posey JE, et al. Congenital diaphragmatic hernia as a prominent feature of a SPECC1L-related syndrome. Am J Med Genet A. 2020;182(12):2919-2925. doi:10.1002/ajmg.a.61878. PMID: 32954677. PMC7988837
59. Abdelhady E, Tobias JD. Perioperative Care of a Four-Year-Old Child With Teebi Hypertelorism Syndrome: A Rare Craniofacial Disorder. J Med Cases. 2026;17(4):141-145. doi:10.14740/jmc5268. PMID: 41821721. PMC12978399
60. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 186–7 (Hypospadias).
61. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 58–61 (Anal anomalies).
62. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 194–7 (Intellectual disability – X-linked inheritance).
63. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 266–9 (Oesophageal and intestinal atresia).
64. Awad BI, AlRajhi B, Alkhaldi A, Alsaab F. Type 1 laryngeal cleft management: a pediatric tertiary care center case series. AME Case Rep. 2025;9:37. doi:10.21037/acr-24-149. PMID: 40330935. PMC12053990
65. European Association of Urology/European Society for Paediatric Urology. EAU Guidelines on Paediatric Urology: Hypospadias (chapter 9). Edn. presented at the EAU Annual Congress London 2026. Arnhem: EAU Guidelines Office; 2026. ISBN 978-94-92671-32-5. Available from: https://uroweb.org/guidelines/paediatric-urology/chapter/hypospadias
66. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; [search 2026-10-29: Opitz G/BBB, MID1, SPECC1L, Teebi]. Available from: https://clinicaltrials.gov
67. Mascaro M, D'Ambrosio L, Lazzari E, Almoguera B, Swafiri ST, Zanchetta ME, et al. A unique missense mutation in the RING domain impairs MID1 E3 ubiquitin ligase activity and localisation and is associated with uncommon Opitz Syndrome-like signs. Biochim Biophys Acta Mol Basis Dis. 2024;1870(4):167126. doi:10.1016/j.bbadis.2024.167126. PMID: 38508475.
68. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; [search 2026-11-01: CDH11, Teebi, Elsahy-Waters]. Available from: https://clinicaltrials.gov
69. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 624–7 (22q11 deletion syndrome).
70. Pinson L, Augé J, Audollent S, Mattéi G, Etchevers H, Gigarel N, et al. Embryonic expression of the human MID1 gene and its mutations in Opitz syndrome. J Med Genet. 2004;41(5):381-6. doi:10.1136/jmg.2003.014829. PMID: 15121778. PMC1735763
71. Fernandez N, Escobar R, Zarante I. Craniofacial anomalies associated with hypospadias. Description of a hospital based population in South America. Int Braz J Urol. 2016;42(4):793-7. doi:10.1590/S1677-5538.IBJU.2015.0568. PMID: 27564292. PMC5006777
72. American Cleft Palate-Craniofacial Association [Internet]. [accessed 2026-10-29]. Available from: https://acpacares.org
73. Face Equality International [Internet]. [accessed 2026-10-29]. Available from: https://faceequalityinternational.org