Cardiac, Facial and Digital Anomalies with Developmental Delay (CAFDADD, TRAF7)

Neurodevelopmental disorder with multiple congenital anomalies caused by germline TRAF7 missense variants

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

The table brings together the identifiers and core data of the entity covered. Suleiman-El-Hattab syndrome, which shares developmental delay, congenital heart disease and distal anomalies with this entity, is another entity, caused by biallelic TASP1 variants, and appears in the last row only to allow the distinction [1–3].

1. Introduction

1.1. Discovery and milestones

Cardiac, facial and digital anomalies with developmental delay (CAFDADD) was delineated in 2018 by Tokita and colleagues, in a joint work by Baylor College of Medicine, the National Institutes of Health and Stanford. The authors brought together seven unrelated individuals, referred for clinical exome sequencing, who shared missense variants in TRAF7 and a picture with four components: developmental delay, congenital heart disease, limb and digit anomalies, and facial dysmorphism. The variant had arisen de novo in six of the seven; in the seventh, the mother was not a carrier and the father was unavailable. Four different variants were identified, and c.1964G>A p.(Arg655Gln) recurred in four patients [13].

The association was supported by statistical and functional arguments. In a cohort of about 7700 undiagnosed exomes from the Baylor laboratory, the excess of de novo missense variants in TRAF7 reached a p-value adjusted for 18,892 genes of 2.6×10⁻³ for the gene and 1.9×10⁻⁸ for the recurrent variant, and all four variants reduced ERK1/2 phosphorylation in transfected cells [13]. Before this work, germline TRAF7 variants had been found in two people with autism spectrum disorder, including the same p.Arg655Gln de novo in a girl, without a disease being established; this last observation came from the 2015 study by Krumm and colleagues on de novo and inherited variants in 2377 families with autism [13, 24]. The gene was known mainly for somatic variants in meningiomas and mesotheliomas [4, 13].

In 2020, Castilla-Vallmanya and colleagues published an international series of 45 patients, recruited by European, North American and Australian centres with the support of the GeneMatcher and DECIPHER platforms. This series defined a recognisable facial gestalt, with blepharophimosis as the most constant feature, described the skeletal defects of the upper trunk and patent ductus arteriosus as the predominant heart defect, showed that germline and somatic variants occupy different positions in the protein and presented the first transcriptomic profile of patient fibroblasts; the authors proposed the name "TRAF7 syndrome" [9]. Case reports and series followed that broadened the phenotype to craniosynostosis and sinus pericranii [25, 26], prenatal diagnosis [27], parental mosaicism with transmission [15], the adult with aortopathy [28] and congenital glaucoma [29].

In 2023 and 2024, two works focused on the heart. Mishra-Gorur and colleagues proposed that TRAF7 participates in a programme common to the neural crest, primary cilia, skull base meningiomas and congenital heart disease, including variants inherited from unaffected parents in patients with non-syndromic heart disease [30]. Pisan and colleagues responded with a cohort of 21 patients and the first compilation of the heart defects of the syndrome, and disputed the pathogenicity of those inherited variants [10, 31]. In 2024, Palma-Milla and colleagues, in Spain, described 11 new patients, reviewed 58 published cases and broadened the cognitive, endocrine and sleep spectrum [17]. In 2026, Xiao and colleagues proposed a unifying mechanism: the syndrome variants stabilise KRAS and NRAS and hyperactivate the MEK–ERK pathway through a dominant-negative effect, in a knock-in mouse model and in cortical organoids derived from a patient's cells [6].

1.2. Nomenclature

OMIM designates the entity as cardiac, facial, and digital anomalies with developmental delay, from which the acronym CAFDADD derives, under number 618164 [4–6]. The entry, created in October 2018 and last revised in January 2020, associates the phenotype with the TRAF7 gene (OMIM 606692) at 16p13.3, with autosomal dominant inheritance, and rests only on the founding series of seven patients; the four variants from that work appear as allelic variants 606692.0001 to 606692.0004, the first of which is p.Arg655Gln. The phenotypic broadening brought by the 2020 and later series (blepharophimosis as the dominant feature, upper trunk defects, deafness in half of the patients) is not incorporated into that entry [4, 9]. The gene entry (606692), created in 2002 and updated in October 2018 with the gene–phenotype relationship, lists the same phenotype as the only one associated with TRAF7 and records the four variants with their respective exons (20, 19, 11 and 12) [12]. Orphanet uses a long descriptive designation, TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndrome (ORPHA:592570), with no registered synonyms [7]. The literature also uses "TRAF7 syndrome" [9], "TRAF7-related multiple congenital anomalies-intellectual disability syndrome" [10] and "TRAF7-related neurodevelopmental disorder" [11]. This article uses CAFDADD.

The TRAF7-associated syndrome, of autosomal dominant inheritance and almost always de novo (OMIM 618164; ORPHA:592570), should not be confused with Suleiman-El-Hattab syndrome (SULEHS) [1]. SULEHS is a different entity: OMIM 618950, gene TASP1 (OMIM 608270) at 20p12.1, autosomal recessive inheritance, described from 2018 onwards by Suleiman, El-Hattab and colleagues in the United Arab Emirates [2, 3, 22, 23, 32]. The two syndromes share developmental delay, congenital heart disease and distal anomalies, which explains the possibility of confusion, but differ in gene, mechanism and recurrence risk. This article covers CAFDADD and describes SULEHS in the differential diagnosis (section 6).

1.3. Definition of the entities in scope

CAFDADD is a multiple congenital anomaly syndrome with developmental delay, caused by heterozygous germline missense variants in TRAF7, concentrated in the WD40 repeat domain and, in smaller numbers, in the coiled-coil domain. The Orphanet definition brings together global developmental delay or regression, variable congenital heart defects (patent ductus arteriosus, atrial or ventricular septal defects, double outlet right ventricle, among others) and dysmorphic features (ptosis, epicanthic folds, dysplastic or low-set ears, low posterior hairline or redundant nuchal skin, widely spaced or inverted nipples, umbilical hernia or diastasis recti and digital anomalies), with inconsistent additional manifestations: tone abnormalities, seizures, deafness, cortical blindness, optic atrophy, cerebral and cerebellar atrophy and hydrocephalus [7].

Outside the entity, and addressed only for contrast, are tumours with somatic TRAF7 variants (meningioma, mesothelioma, adenomatoid tumour, intraneural perineurioma and others), which are findings restricted to tumour tissue and have no germline implication [8, 30]. Also outside are rare TRAF7 variants inherited from healthy parents in children with non-syndromic congenital heart disease, whose pathogenicity remains disputed (section 2.7) [10, 30, 31].

2. Molecular Genetics and Pathophysiology

2.1. The gene and the protein

TRAF7 is located at 16p13.3, has 21 exons and encodes, in the longest isoform, a protein of 670 amino acids [13]. The MANE Select transcript is NM_032271.3 (protein NP_115647.2); the founding article used version NM_032271.2, and the c. positions cited there coincide with those of version 3 [13, 14]. From the amino to the carboxyl terminus, the protein has a RING domain, a TRAF-type zinc finger, a coiled-coil segment and seven WD40 repeats. The WD40 repeats distinguish TRAF7 from the other members of the family (TRAF1 to TRAF6), which end in a TRAF domain; the coiled-coil and the zinc finger mediate homodimerisation and cellular localisation, and the WD40 repeats bind partners such as MEKK3 (MAP3K3) [9, 13]. The protein was identified in 2004 in a proteomic mapping of the interactions of the TNFα/NF-κB pathway, by tandem affinity purification and mass spectrometry, as a partner of MEKK3; the mutagenesis and co-immunoprecipitation assays of that work located the binding to MEKK3 in the WD40 repeats and dimerisation in the central TRAF and coiled-coil domains, showed a cytoplasmic vesicular distribution independent of MEKK3, and indicated that MEKK3 phosphorylates the N-terminal region of TRAF7 and promotes its ubiquitination; a fragment with the RING domain was ubiquitinated in the presence of E1 and E2 enzymes, the first indication of E3 ligase activity [12]. In that system, co-expression of normal TRAF7 and MEKK3 synergistically activated NF-κB and AP1 reporters, which contrasts with the restrictive effect on NF-κB described in later works, which showed degradation of NEMO and RELA; the difference reflects reporter assays with overexpression versus studies of degradation of endogenous pathway components [8, 12].

TRAF7 is a ubiquitin and SUMO E3 ligase. In cellular studies, it enhances the activation of JUN/AP1 and DDIT3 (CHOP) in synergy with MEKK3; it restricts the nuclear factor κB (NF-κB) pathway by adding lysine 29-linked polyubiquitin chains to NEMO (IKBKG) and RELA (p65), which are directed to lysosomal degradation; it attenuates the antiviral signalling of RIG-I-like receptors through lysine 48-linked ubiquitination of TBK1; it ubiquitinates p53, negatively regulates c-Myb by sumoylation and, in endothelial cells, binds ROBO4 and reduces hyperpermeability [8, 9]. In the mouse, complete absence of Traf7 is lethal at mid-gestation through loss of endothelial integrity, with reduced Klf2 expression; postnatal endothelial deletion causes severe cerebral haemorrhage; TRAF7 binds SCRIB through the N-terminal region and MEKK3 through the WD40 domain and is required for shear stress-induced ERK5 phosphorylation, in the MEKK3–MEK5–ERK5 pathway [33].

In the mouse embryo, Traf7 is expressed in the neural tube from embryonic day 8.5, overlapping with the neural crest marker Sox10, and at day 10.5 in the heart, the trigeminal and geniculate ganglia and the first and second branchial arches; expression in the meninges is high [30]. This distribution coincides with the tissues affected in the syndrome: face, skull, heart and auditory pathways. In a Croatian study of embryonic and fetal kidneys, TRAF7 expression was decreased in all the congenital anomalies of the kidney and urinary tract examined (duplex, horseshoe, hypoplastic and dysplastic kidney), an expression finding without genetic demonstration [34].

2.2. Disease mechanism

The mechanism is not haploinsufficiency. ClinGen dosage curation assigns a score of 0 to both haploinsufficiency and triplosensitivity [16]; in gnomAD v4, TRAF7 has a probability of loss-of-function intolerance (pLI) of 0.000012 and an upper bound of the observed/expected ratio for loss of function (LOEUF) of 0.646, with 45 loss-of-function variants observed against 89.3 expected, whereas the missense Z-score is 3.39 [35]. The works from 2020 to 2026 cite a pLI of 0.02, calculated in gnomAD v2.1 [9, 10]. In both versions, heterozygous loss of function is under little selection, and the constraint falls on missense substitutions. Consistently, 16p13.3 deletions that include the whole gene do not reproduce the syndrome, and ClinVar records no pathogenic truncating intragenic variants [19]. The concentration of recurrent missense variants in the WD40 domain led Castilla-Vallmanya and colleagues to propose a gain of function or a dominant-negative effect [9].

The effect on the MAP kinase (mitogen-activated protein kinase) pathway has been described in opposite directions. In 2018, overexpression of the four variants in HEK293T cells did not alter p38, JNK or total ERK1/2, but reduced ERK1/2 phosphorylation after TNFα stimulation, with statistical significance for p.(Arg655Gln), p.(Thr601Ala) and p.(Arg371Gly) in three experiments; the authors related this result to the craniofacial, cardiovascular and limb anomalies of the mouse with conditional loss of Erk2 [13]. In 2026, Xiao and colleagues showed that TRAF7 binds KRAS and NRAS through the WD40 domain and promotes their polyubiquitination and proteasomal degradation; the syndrome variants, from both the WD40 and the coiled-coil, form heterodimers with the normal protein and abolish this function through a dominant-negative effect, which accumulates KRAS and NRAS without a change in messenger RNA and increases MEK1/2 and ERK1/2 phosphorylation in the brain and heart at birth and in cortical neurons; HRAS, RRAS, MEKK3, p38 and JNK were unchanged, and CDC42 and RAC1 were also stabilised [6]. The divergence between the two results reflects different experimental systems (overexpression in a cell line versus an endogenous allele in the mouse and in human organoids).

The Traf7 p.R654Q/+ mouse model, equivalent to human p.(Arg655Gln), reproduces several aspects of the disease. Homozygotes were present in 4 of 40 blastocysts, but none among 186 pups from heterozygote crosses on postnatal day 9, which indicates biallelic embryonic lethality. Heterozygotes had growth delay between weeks 1 and 8, a shorter and narrower skull with patent sutures, limb defects, late ocular manifestations (ptosis, exophthalmos, corneal opacity; 124 of 162 animals older than 8 weeks had only ocular changes), a thinned left ventricular wall with reduced ejection fraction and fractional shortening, deficits in social memory and spatial learning and reduced motor activity; magnetic resonance imaging showed increased grey matter volume in the cerebellum, hippocampus, hypothalamus and septum and a reduction in the motor cortex [6]. The authors point out that the hypoplastic left ventricle of the mouse does not correspond to the human cardiac spectrum, dominated by patent ductus arteriosus [6].

In cortical organoids derived from induced pluripotent stem cells of a Chinese girl with p.(Arg655Gln), compared with her healthy father and with a CRISPR-corrected isogenic control, growth decreased from day 19, the neural tubes were smaller, there were fewer Ki67+ progenitors, premature neural differentiation with depletion of the progenitor pool, incomplete neuronal maturation and altered network activity [6, 36]. The authors frame CAFDADD as a disorder related to the RAS–MAPK pathway, but point out clinical differences from the classic RASopathies (section 6) [6].

A third axis, cilia, was proposed by Mishra-Gorur and colleagues. In zebrafish and Xenopus, knockdown of traf7 with morpholinos caused cardiac looping defects, pericardial oedema, ventricular dysfunction, craniofacial defects and reduction of sox10 and twist; injection of messenger RNA with germline variants (V442M, T601A) reproduced pericardial oedema, craniofacial defects and neural crest disturbance. Ciliopathy features also appeared (curved axis, hydrocephalus, renal cysts, loss of primary and motile cilia, altered pitx2c in the left–right organiser), and the mutant proteins lost their interaction with IFT57, a component of the intraflagellar transport complex B, and with CYLD [30]. The authors propose loss of primary cilia in the neural crest as a theme common to skull base meningiomas and congenital heart disease [30].

Fibroblasts from patients with WD40 variants show no change in TRAF7 expression, but have NOTCH3 reduced by half, FLNB increased more than twofold, IGFBP7 reduced fourfold and reduction of BCL2 and PTGS2. RNA sequencing identified 76 differentially expressed genes under basal conditions and 90 after TNFα, seven of which were confirmed (ANGPT1, CASK, KIF26B, WNT5A, CFD, GPC6, KAZALD1), with enrichment in axon guidance, the Wnt/Ca²⁺ pathway and NFAT signalling in cardiac hypertrophy [9]. This profile is a research tool, and there is no measurable biochemical deficiency that could serve as a clinical test [8].

2.3. Inheritance

Inheritance is autosomal dominant [4, 7, 16]. OMIM summarises the variants of the founding article as all de novo; the article confirms de novo origin in six patients and, in the seventh, only absence in the mother, with the father unavailable [4, 13]. In the series of 45 patients, 36 cases were sporadic de novo, one resulted from low-level maternal mosaicism, five had unknown inheritance and in one family two affected dizygotic twins inherited the variant from their affected mother, in whom the variant had arisen de novo [9]. In the Pisan cohort, a 43-year-old patient with p.(Leu625Phe) transmitted the variant to two affected offspring [10]. In an African-American family from Texas, a 31-year-old mother, mosaic with 33.89% variant allele in leucocytes and with patent ductus arteriosus, intellectual disability and ptosis, transmitted c.1936G>A p.(Val646Ile) to her son, who was constitutionally heterozygous [15]. GeneGuidance keeps the inheritance as "unknown" at the gene level, because there are somatic associations, and autosomal dominant at the disease level [8].

2.4. Variant spectrum

All intragenic variants securely associated with the syndrome are missense, with one in-frame deletion classified as likely pathogenic in ClinVar [6, 19]. By 2026, 31 variants had been compiled in 96 patients: 24 in the WD40 domain and 7 in the coiled-coil; p.(Arg655Gln) was present in 30 patients (31.3%) [6]. The recurrence of this variant is explained by its location at a CpG dinucleotide [13]. In the 2020 series, the variants occupied 20 amino acid positions, with recurrence at 8, and two residues had two different substitutions, Ser558 (Phe or Tyr) and Phe617 (Leu or Ser) [9]. The table brings together the variants cited in this article, with nomenclature confirmed in VariantValidator (GRCh38, NM_032271.3) or, where indicated, only in ClinVar.

The variants p.(Val142Met) and p.(Val442Met) were published only in protein notation; the c. notations in the table correspond to the only substitutions that produce these changes (Val→Met requires G>A at the first codon position), confirmed in VariantValidator and not read in the article [14, 30]. In one of the Polish reports, the second case appears in one sentence as "p.(His595Asp)"; the genomic coordinate and the rest of the article correspond to c.1783C>G p.(Leu595Val), which is the correct notation [14, 37]. Other variants classified as pathogenic or likely pathogenic in ClinVar include p.(Arg524Gln), p.(Leu625Val), p.(Ser629Asn), p.(Phe617Leu), p.(Phe617Ser), p.(Gly518Val), p.(Glu436Lys), p.(Met633Ile), p.(Ser663Thr), p.(Gly375Asp), p.(Thr425Ser) and the in-frame deletion c.1543_1545del p.(Glu515del); of the 59 pathogenic or likely pathogenic records associated with the gene, the rest are 16p13.3 copy number variants classified on the basis of contiguous genes (for example TSC2 and PKD1), and not on loss of TRAF7 [19].

2.5. Gene–disease validity and constraint

ClinGen, through the intellectual disability and autism expert panel, classified on 6 September 2023 the relationship between TRAF7 and complex syndromic neurodevelopmental disorder with autosomal dominant inheritance as definitive [16]. The missense Z-score (3.34 in the founding article; 3.39 in gnomAD v4) indicates moderate constraint on amino acid substitutions, which contrasts with tolerance to loss of function [13, 35]. These metrics support the application of the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) functional domain and rarity criteria to WD40 missense variants and advise against classifying truncating TRAF7 variants as pathogenic by analogy alone [10, 28].

2.6. Genotype–phenotype correlations and expressivity

The correlation between position and phenotype is limited by the number of patients. In the 2020 series, three patients with coiled-coil variants of unknown inheritance (patients 1, 2 and 4) had an only partially overlapping picture, with neurodevelopmental disorder and seizures in two, without the facial gestalt; they were classified as carriers of variants of uncertain significance and excluded from the core cohort of 42. The only patient with a de novo coiled-coil variant had the typical facies [9]. In the founding article, the two coiled-coil variants, p.(Lys346Glu) and p.(Arg371Gly), were associated with complete pictures [13], and the 2026 model attributes the same dominant-negative effect to variants in both domains [6]. No phenotype specific to p.(Arg655Gln) has been described: this variant occurs in patients ranging from the newborn with severe heart disease to the adult with borderline intellectual disability and aortic root aneurysm [13, 28].

Expressivity varies within the same family. In the twins with p.(Phe617Leu), only one had heart disease; in the family with p.(Val646Ile), the mosaic mother had polydactyly and dysmorphic features that her constitutionally heterozygous son did not have, while the son had an atrial septal defect, a congenital maxillary frenulum and intestinal malrotation [15, 31]. In the mosaic patient of the founding article (13–15% in blood), a boy assessed at 8 years and without heart disease, the picture was not milder [12], which the authors attribute to the variable proportion of mutated cells in the critical tissues [13].

2.7. Inherited variants in non-syndromic congenital heart disease

In the cohort of the Pediatric Cardiac Genomics Consortium and the Pediatric Heart Network (2645 trios and 226 singleton cases), Mishra-Gorur and colleagues found three children with rare TRAF7 variants inherited from an unaffected parent, without a syndromic facies: p.(Val142Met) with tricuspid atresia and heterotaxy with L-transposition; p.(Val442Met) with hypoplastic right ventricle and pulmonary atresia; c.1998+2T>G with truncus arteriosus; one had oligodactyly of the right hand and another polycystic kidney disease. The authors proposed incomplete penetrance [30]. Pisan and colleagues disputed this: non-penetrance had never been described in the syndrome, p.(Val142Met) is present in 4 of 192,850 alleles in gnomAD v2, a canonical splice variant implies loss of function in a tolerant gene, the number of missense variants with CADD ≥26 (2 in 2871) does not exceed that expected in controls, and the phenotypes (heterotaxy with renal cysts, severe limb defects with truncus) do not belong to the known spectrum [10]. In their reply, the authors invoked the effect of p.(Val442Met) in animal models, pathogenicity predictions (AlphaMissense, MetaSVM, REVEL), the absence of c.1998+2T>G from gnomAD v4, ocular and electrocardiographic changes in the heterozygous mouse of the International Mouse Phenotyping Consortium and the exclusion of isolated patent ductus arteriosus from the consortium [31]. The question remains open; these variants do not, for now, serve as a basis for genetic counselling.

2.8. Somatic allelic disorders and germline–somatic separation

Somatic TRAF7 variants are present in about a quarter of meningiomas and in all of the secretory subtype, typically with a second alteration in KLF4 (p.K409Q), AKT1 or PIK3CA; they also occur in mesotheliomas, adenomatoid tumours of the genital tract and intraneural perineuriomas [8, 30], and have been described in a paediatric myxoid and spindle cell mesenchymal tumour after transplantation [38]. Orphanet records TRAF7 as a gene with causal somatic variants in meningioma (ORPHA:2495) [39]. TRAF7 meningiomas are located at the skull base anterior to the foramen magnum and on the convexities anterior to the coronal suture, territories of neural crest-derived meninges; 93% of the somatic variants lie in the WD40 domain, with a predominance of Asn520 and Gly536 [30]. In the ESMO (European Society for Medical Oncology) handbook, TRAF7 is on the list of alterations with an emerging predictive role in meningioma, without reaching level I of the ESCAT scale [40].

Germline and somatic positions are almost mutually exclusive: p.(Arg655Gln) has never been described in tumours; variants at Asn520, recorded 39 times in meningiomas, have never been found in syndromic patients; p.(His521Arg) and p.(Ser561Arg) recur in adenomatoid tumours; Leu519 is replaced by phenylalanine in the syndrome and by proline or arginine in meningiomas. The only overlap is p.(Arg524Trp), in a meningioma that also had an SMO variant of uncertain oncogenicity. The authors consider that the somatic variants, if present in the germline, may be lethal [9]. It follows that a somatic TRAF7 finding in a meningioma has no germline implication, and that a germline TRAF7 variant in a child indicates CAFDADD and not an established predisposition to meningioma [8].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and limits

Clinical knowledge rests on three cohorts with individual data read in full text: the founding article, with 7 patients aged between 1 week and 43 years (2 female, 5 male) [13]; the international series of 45 patients, analysed in a core cohort of 42 that excludes three carriers of coiled-coil variants of uncertain significance [9]; and the cohort of 21 patients of Pisan and colleagues, aged 11 months to 46 years (13 male) [10]. The Spanish review of 69 cases (11 new and 58 published) was read only in abstract [17]. All are series of patients diagnosed by sequencing, with retrospective data collection, without a population denominator and with selection for complete pictures; patients assessed in childhood predominate, and the frequencies reflect disease already under care, not natural history without intervention. The frequencies in the table are absolute counts: a missing record does not equate to absence of the feature.

Source: tables and text of Tokita and colleagues (2018), Castilla-Vallmanya and colleagues (2020) and Pisan and colleagues (2024) [9, 10, 13] (Pisan counts by tabulated feature; cardiac counts of Castilla-Vallmanya and Pisan according to the Pisan compilation) [10].

3.2. Prenatal and neonatal period

Onset is prenatal or neonatal [7]. In the founding article, prenatal ultrasound had detected heart disease in 3 of 7 pregnancies, cystic hygroma in 2, single umbilical artery in 2, intrauterine growth restriction in 1 and choroid plexus cyst in 1; after birth, 4 newborns had respiratory distress and 3 feeding difficulties, and one suffered cardiorespiratory arrest requiring extracorporeal membrane oxygenation, complicated by intracranial haemorrhage [13]. In the 2020 series, 24 of 42 patients had feeding difficulties, often with tube feeding in the first year [9]. One of the Polish reports describes a short two-vessel cord and jaundice treated with phototherapy [37]. Prenatal diagnosis by exome sequencing of chorionic villi was published after sonographic detection of structural anomalies, with ventricular septal defect and double outlet right ventricle [10, 27].

3.3. Neurodevelopment and behaviour

All patients in the 2020 series had some degree of developmental delay; intellectual disability was recorded in 23 of 42, language delay in 29, motor delay in 30, hypotonia in 17, autism spectrum disorder in 6 and epilepsy in 7 [9]. In the founding article, one boy had normal early development followed by regression and severe autism, tone varied between hypotonia, hypertonia and leg stiffness, and there were documented seizures in two patients and possible absences in a third [13]. The review of 69 cases added that the cognitive spectrum is broader than initially described: some patients reach normal development despite initial psychomotor delay, expressive language is disproportionately affected and frequently requires augmentative and alternative communication, and autistic traits, especially behavioural rigidity, are common [17]. In 2025, a patient with TRAF7-related neurodevelopmental disorder without developmental delay or intellectual disability was published in Japan; only the title and metadata were consulted [11].

In the Polish report of the second case, the child sat at 12 months, walked at 2 years and at 16 months had no expressive language, although she understood [37]. In the 36-year-old Korean adult, the intelligence quotient on the Wechsler Adult Intelligence Scale was 75 (borderline intellectual disability), with special education schooling and without independent living [28]. The 2024 authors also describe sleep disorders [17].

3.4. Central nervous system and skull

Magnetic resonance imaging mainly shows non-specific changes, with enlarged ventricles [9]. In the founding article, four of seven patients had prominent ventricles or cerebral atrophy, two had variant venous anatomy, one hydrocephalus, another syringohydromyelia from C5 to T12 and a third possible polymicrogyria; three had a tethered cord [13]. Accogli and colleagues described, in Genoa, two patients with p.(Arg655Gln) and p.(Leu402Val) with a "pear-shaped" skull due to multiple craniosynostosis, sinus pericranii (an abnormal communication between the intracranial venous sinuses and epicranial veins), anomalies of the skull base and the craniocervical junction, dysgyria and hypoplasia of the inferior cerebellar vermis [25]. In Adelaide, a child with multisutural craniosynostosis and p.(Arg524Trp) was published [26]. In one of the Polish cases, MR angiography showed hypoplasia of the middle and anterior segments of the sagittal sinus with peripheral venous circulation [37]. Craniosynostosis was present in 3 of 42 patients in the 2020 series, and other changes in skull shape (trigonocephaly, dolichocephaly, plagiocephaly, brachycephaly, bitemporal narrowing) in 18 [9].

3.5. Face

Changes in the palpebral fissures are almost universal. In the 2020 series, there was blepharophimosis in 33 of 42 patients, epicanthus in 20, ptosis in 19, telecanthus in 14 and slanting fissures in 11; hypertelorism in 17, ear anomalies (low-set, posteriorly rotated, prominent ears) in 27, a bulbous nasal tip in 17, a broad or flat nasal root in 11, mild micrognathia or retrognathia in 13, a high or prominent forehead in 11 and palatal anomalies (submucous cleft, velopharyngeal insufficiency) in 15 [9]. In the founding article, multiple hair whorls were present in 3 of 7 and a low posterior hairline or redundant nuchal skin in 5, two of them with prenatal hygroma [13]. The 2024 review added arched eyebrows to the gestalt [17]. In the infant, oedematous eyelids with fissures opening only 2 to 3 mm, associated with ophthalmoplegia, led to exclusion of myasthenia and initial suspicion of blepharophimosis, ptosis and epicanthus inversus syndrome [37].

3.6. Heart and great vessels

Congenital heart disease is the most severe manifestation and the main cause of early complications [17, 41]. Patent ductus arteriosus (PDA) is the most frequent lesion, followed by septal and valvular defects [10]. In the 2020 series, there was PDA in 24 of 42 patients, many with surgical correction, atrial septal defect (ASD) in 9, ventricular septal defect (VSD) in 6 and valvular anomalies in 10 [9]. The founding article concentrated the most severe forms: supravalvular pulmonary stenosis with PDA; severe aortic coarctation with parachute mitral valve, supravalvular mitral ring and hypoplastic left ventricle; double outlet right ventricle with pulmonary atresia and hypoplastic left heart; double outlet with mitral atresia and univentricular physiology; and bicuspid aortic valve (BAV) with moderate aortic stenosis, large PDA and prolonged QT interval [13]. GeneGuidance also mentions conduction abnormalities [8].

Source: compilation by Pisan and colleagues (2024) from the series cited, with the case of Kim and colleagues (2024) [10, 28]. The Pisan table includes the lesions of the three patients from the heart disease consortium (tricuspid atresia, double outlet left ventricle, L-transposition, truncus, hypoplastic right ventricle, pulmonary atresia), which were not carried over because their relationship with the syndrome is disputed (section 2.7). For the 2020 series, the compilation records 8 ASDs and 5 VSDs, whereas the original text gives 9 and 6 [9].

Aortopathy is a manifestation of the adult. In the Korean patient, the ascending aorta measured 45 mm on a transthoracic echocardiogram (TTE) with a poor acoustic window due to pectus carinatum; two years later, CT angiography showed an aortic root aneurysm of 58 mm at the sinus of Valsalva, BAV and aortic regurgitation, treated by Bentall surgery [28]. In the 2020 series and the 2024 cohort there is one aortic aneurysm in each [10]. The magnitude of the aortic risk in the syndrome is not quantified.

3.7. Skeleton, limbs and trunk

The upper trunk gestalt combines a short neck with sloping shoulders (24 of 42), pectus carinatum (17 of 42) and relative macrocephaly; there were other thoracic anomalies in 10, rib anomalies in 5, spinal deviations in 7 and vertebral anomalies in 14, and cervical stenosis or spinal cord compression was a clinical concern in several patients [9]. In the extremities, the series recorded finger deviations (10), camptodactyly (10), brachydactyly (6), syndactyly (5), overlapping toes (10), flat foot (10), varus or valgus deviations (10) and a gap between the first and second toes (5), with joint limitation, hypermobility and occasional dislocations [9]. In the founding article, all seven had some limb involvement: variant palmar or digital creases (6), overlapping toes (5), clinodactyly (3) and contractures (2); the 43-year-old woman had scoliosis with degenerative joint disease, an asymmetric sternum, bilateral avascular necrosis of the hip, tibial malformation, valgus ankles, flexion contractures of the hands and subluxation of several joints of the hands and feet [13]. The Korean adult had short stature (153.7 cm, below the 3rd centile), a dorsal hump, arachnodactyly, lumbar scoliosis and severe angulation of the craniocervical junction with spinal cord compression [28]. One of the Polish cases had clubfoot treated with casts and orthoses [37].

3.8. Hearing and vision

Conductive, sensorineural or mixed deafness was present in 21 of 42 patients; refractive errors and strabismus in 10 each [9]. In the founding article there was cortical blindness in one patient and optic atrophy in two [13]. The Korean adult had bilateral blindness since childhood, without light perception, with optic atrophy and low-amplitude visual evoked potentials, in addition to hearing impairment [28]. In 2026, primary congenital glaucoma in a patient with CAFDADD was published in Madrid, consulted only as title and metadata [29].

3.9. Growth, feeding, endocrine, renal and other systems

In the 2020 series, short stature affected 12 of 42 patients, low weight 5, and microcephaly or macrocephaly 10 [9]. The 2024 review describes endocrine manifestations, including growth deficiency, without detail accessible in the abstract [17]. There were renal anomalies in 10 of 42, cryptorchidism in 7, hernias in 11, inverted nipples in 6 and lower limb oedema in 3 [9]; the Polish reports describe left pelvicalyceal dilatation and duplication, with urinary tract infection in one of them [37]. Intestinal malrotation was described in an infant from the family with maternal mosaicism and in a patient with p.(Arg655Gln) in the Korean supplementary material [15, 28].

3.10. Sleep and airway

Sleep disorders are part of the spectrum [17]. The Korean adult had snored since childhood; after aortic surgery he had dyspnoea and nocturnal desaturations, and polysomnography revealed severe obstructive sleep apnoea syndrome (OSAS), with an apnoea–hypopnoea index of 88 per hour and minimum saturation of 74%, attributed to narrowing of the naso- and oropharynx due to a retropositioned mandible, aggravated by the short neck and the vertebral anomaly; continuous positive airway pressure ventilation relieved the symptoms, and the authors attributed the right ventricular dilatation to OSAS [28].

3.11. Adulthood and ageing

Among the seven patients older than 18 years in the 2020 series, two women aged 20 and 44 had progressive hair loss, the 44-year-old also premature atherosclerosis, and a 26-year-old man had premature osteoporosis and hair loss; the authors interpret these findings as possible signs of premature ageing [9]. The 2024 cohort includes adults up to 46 years of age and a transmission from a 43-year-old patient [10]. Data on adulthood are limited to these cases, and there are no survival studies.

3.12. Tumours

No tumour had been reported in patients with germline WD40 domain variants up to 2020, in a series with few adults; a 43-year-old patient from the Tokita cohort had a meningioma, according to Castilla-Vallmanya, and one of the carriers of a coiled-coil variant of uncertain significance had endometrioid adenocarcinoma at 36 years [9]. As meningiomas with somatic TRAF7 generally require a second variant in KLF4, AKT1 or PIK3CA, the germline variant alone may not suffice [9]. Xiao and colleagues suggest, from the stabilisation of CDC42 and RAC1, a possible mechanism for an age-dependent meningioma risk, which they consider a hypothesis to be tested in longitudinal studies [6]. The tumour risk associated with the germline variant is not established.

4. Clinical Recognition and Warning Signs

4.1. When to suspect

In the prenatal period, the association of congenital heart disease with cystic hygroma, increased nuchal translucency or nuchal oedema, single umbilical artery or intrauterine growth restriction is compatible with the syndrome, but not specific to it; the published prenatal diagnosis started from structural anomalies on ultrasound [13, 27].

In the newborn and infant, suspicion arises in the presence of congenital heart disease, especially PDA, septal or valvular defects, combined with blepharophimosis, ptosis or epicanthus, redundant nuchal skin or a low posterior hairline, low-set and dysplastic ears, widely spaced or inverted nipples, overlapping toes or other digital anomalies and feeding difficulties [9, 13]. Oedematous eyelids with narrow fissures may suggest myasthenia or blepharophimosis, ptosis and epicanthus inversus syndrome, and heart disease with dysmorphism suggests a RASopathy [13, 37].

In the child, the guiding signs are developmental delay with disproportionately affected expressive language, conductive or sensorineural deafness, a short neck with sloping shoulders and pectus carinatum and changes in skull shape [9, 17]. A recognisable gestalt allowed, in two patients in the 2020 series, diagnosis by targeted sequencing based on clinical suspicion [9].

In the adolescent and adult, especially when the diagnosis was not made in childhood, attention should be paid to the combination of mild or borderline intellectual disability with blepharophimosis, short stature, a short neck, pectus carinatum, BAV or aortic root dilatation, which may be confused with a connective tissue disorder, and to signs of premature ageing [9, 28].

4.2. Warning signs and emergencies

The situations requiring immediate action documented in the syndrome are cardiovascular, respiratory and neurological. In the newborn, cyanosis, hypoperfusion or collapse suggest duct-dependent heart disease (pulmonary atresia, hypoplastic left heart, mitral atresia, severe coarctation), already described in the syndrome; one patient suffered cardiorespiratory arrest requiring extracorporeal oxygenation [13]. Neonatal respiratory distress occurred in 4 of 7 patients [13]. Cervical stenosis and spinal cord compression were a clinical concern in several patients, and severe angulation of the craniocervical junction with spinal cord compression was documented in one adult, so motor deficit, gait disturbance or signs of myelopathy require targeted spinal imaging [9, 25, 28]. In the adult, new-onset dyspnoea may reflect rapid growth of an aortic root aneurysm with valvular regurgitation or severe OSAS [28]. Developmental regression has been described in one patient and should be assessed as a warning sign [7, 13].

4.3. Newborn screening

The syndrome is not the subject of newborn screening; there is no biochemical biomarker.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no published clinical diagnostic criteria. The diagnosis is molecular: it requires a heterozygous TRAF7 variant classified as pathogenic or likely pathogenic in a patient with a compatible phenotype [8, 16]. The facial and upper trunk gestalt guides suspicion and variant interpretation, and the 2020 series developed a composite facial image by computational analysis [9].

5.2. Genetic tests in order

The 2021 ACMG guideline recommends exome or genome sequencing as a first- or second-tier test in paediatric patients with congenital anomalies with onset before 1 year or with developmental delay or intellectual disability with onset before 18 years, because it has a higher yield than conventional tests [18]. Almost all patients in the 2020 series were diagnosed by trio exome sequencing; two by a neurocristopathy and craniofacial malformation panel that included TRAF7; and two by clinical suspicion, with targeted Sanger sequencing or reanalysis of an unsolved singleton exome [9]. In the Korean adult, karyotype and microarray were normal and the diagnosis emerged from a clinical exome of about 7000 genes, with Sanger confirmation and parental testing [28].

In congenital heart disease, the 2018 American Heart Association (AHA) scientific statement justifies genetic testing on the grounds of recurrence risk, extracardiac involvement and prognosis, and describes the increasing use of next-generation sequencing [42]. In a Chinese series of 101 children with congenital heart disease studied by microarray and trio exome sequencing, the combined yield was 28.7% (20.8% chromosomal, 7.9% sequence), 61.5% with extracardiac features and 17.3% in isolated heart disease (p = 4.6×10⁻³); a de novo TRAF7 missense variant was found in a child classified as having isolated heart disease, which the authors attribute to extracardiac features not yet recognised at the age of assessment [43].

The first-line test for suspected CAFDADD is therefore the exome, preferably trio, or a multigene panel for neurodevelopmental disorders, congenital anomalies or congenital heart disease that includes TRAF7. Microarray retains a place in the general work-up of the child with congenital anomalies, but does not detect the causal missense variants, and a 16p13.3 deletion that includes TRAF7 does not explain the syndrome [19, 35]. The most relevant non-molecular investigations are echocardiography, audiological assessment, developmental and behavioural assessment, endocrine assessment of growth and brain imaging [8].

5.3. Limits of the tests

The exome and panels detect single nucleotide substitutions in the coding regions of TRAF7, which make up the whole known spectrum; the sources consulted do not describe deep intronic variants, small structural rearrangements or regulatory variants as a cause of the syndrome. Mosaicism is the most relevant practical limit: the allele fraction in blood was 13% on the exome and 15% on high-depth targeted sequencing in a patient with a complete picture, and 33.89% in an affected mother [13, 15]. Low-level maternal mosaicism was documented in the 2020 series [9]. A negative exome does not exclude the syndrome in the presence of a typical picture; targeted review of the TRAF7 reads, high-depth sequencing or the study of another tissue is warranted.

5.4. Interpretation and report content

The report should state the gene, the transcript with version (NM_032271.3), the variant in Human Genome Variation Society (HGVS) nomenclature, c. and p., zygosity, the allele fraction when it suggests mosaicism, the parental origin when studied and the ACMG/AMP class with the criteria applied. In the Korean case, p.(Arg655Gln) was classified as pathogenic with criteria PS2 (confirmed de novo), PM1 (functional domain), PM2 (absence from population databases), PP1, PP2 and PP3 [28]. Classification of novel variants relies on location in the WD40 or coiled-coil domain, absence from gnomAD, de novo occurrence and overlap with the phenotype [9, 10]. Reclassification over time is real: p.(Leu595Val), classified as of uncertain significance by the authors in 2021, is now likely pathogenic in ClinVar [19, 37].

Three situations call for caution. Coiled-coil variants of unknown inheritance in patients without the gestalt were kept as of uncertain significance in the 2020 series [9]. Variants inherited from healthy parents in non-syndromic heart disease have disputed pathogenicity [10, 31]. Truncating variants and deletions of the gene do not correspond to the known mechanism [16, 35]. In all of them, segregation studies, targeted clinical reassessment (eyes, ears, upper trunk, hearing, heart) and periodic reanalysis are the decision tools.

5.5. Prenatal and preimplantation diagnosis

In the presence of fetal structural anomalies, prenatal exome sequencing of chorionic villi made it possible to identify p.(Leu519Phe) and support the decision about the pregnancy [27]. The North American recommendations cited by the AHA advocate microarray when invasive diagnosis is performed for a sonographic anomaly [42]; as microarray does not detect the variant, the exome is the test that can establish the diagnosis. When the familial variant is known, targeted prenatal diagnosis and preimplantation genetic testing are technically applicable (section 8).

5.6. Practical algorithm

6. Differential Diagnosis

6.1. Comparative table

Sources: SULEHS [23, 45]; RASopathies [6, 13]; Ohdo-type syndrome [9]; BPES [37]; connective tissue disorders [28]; non-syndromic heart disease [10, 30]; tumours [8, 9]. The features of the differential entities correspond to those the cited authors use for the distinction, and not to a complete description of these diseases.

6.2. RASopathies

The overlap with the RASopathies is clinical and, in the light of 2026, mechanistic. In the founding article, the hypotheses before the exome were cardiofaciocutaneous syndrome in one patient and the Noonan spectrum in another, and the 43-year-old woman was reminiscent of Costello syndrome because of her coarse facies, heart disease, scoliosis and contractures [13]. In the 2020 series, eight patients had undergone Noonan or RAS–MAPK pathway panels before diagnosis [9], and one of the Polish reports had a prior suspicion of RASopathy [37]. Xiao and colleagues, although they demonstrate hyperactivation of the MEK–ERK pathway, point out differences: intellectual disability tends to be more severe than in Noonan syndrome; the typical heart disease of Noonan syndrome is pulmonary valve stenosis and hypertrophic cardiomyopathy, whereas CAFDADD has mainly PDA and septal and valvular defects; lymphatic anomalies are not systematically described; and no juvenile myelomonocytic leukaemia or myeloproliferative disorders have been recorded [6]. Blepharophimosis and a short neck with pectus carinatum point towards TRAF7; a negative RAS–MAPK panel in a child with this picture should lead to exome sequencing.

6.3. Blepharophimosis syndromes

Blepharophimosis, present in 33 of 42 patients, brings CAFDADD close to the group of blepharophimosis syndromes with intellectual disability; five patients in the 2020 series had undergone KAT6B sequencing for suspected Ohdo-type syndrome [9]. In the Polish infant, exome sequencing was requested for suspected blepharophimosis, ptosis and epicanthus inversus syndrome, and myasthenia was excluded by repetitive stimulation and acetylcholine receptor antibodies [37]. BPES is characterised by blepharophimosis, ptosis, epicanthus inversus and telecanthus, with premature ovarian insufficiency in type I, and does not have the cardiac and skeletal complications of CAFDADD; the authors recommend excluding CAFDADD when BPES is suspected [37].

6.4. Connective tissue disorders with aortopathy

In the adult with aortic root dilatation, BAV, pectus carinatum, scoliosis and arachnodactyly, the Korean authors considered Loeys-Dietz syndrome the most similar, followed by Marfan syndrome and the forms of Ehlers-Danlos with root aneurysm; karyotype and microarray were normal and the exome identified TRAF7 [28]. The 2022 ACC/AHA guideline recommends genetic assessment in BAV with hereditary thoracic aortic disease or with Loeys-Dietz features [46]. Blepharophimosis, deafness and intellectual disability help distinguish CAFDADD from these entities.

6.5. Suleiman-El-Hattab syndrome (TASP1)

SULEHS was described in 2018 in an infant from the United Arab Emirates with a homozygous deletion at 20p12.1 that included exons 5 to 10 of TASP1, developmental delay, acquired microcephaly, distinctive facies and skeletal, cardiac and renal anomalies [32]. In 2019, four unrelated children with biallelic loss-of-function variants (a homozygous founder deletion of exons 5 to 11 in two, p.(Thr234Met) at the active site and p.(Arg67*)) confirmed the entity: developmental delay with hypotonia and microcephaly, feeding difficulties with poor weight gain, recurrent respiratory infections, cardiovascular malformations, cryptorchidism, happy demeanour and distinctive facies [23]. Taspase 1 cleaves and activates the histone methyltransferases KMT2A and KMT2D, which relates SULEHS to Wiedemann-Steiner and Kabuki syndromes [23]. In 2022, six additional patients showed absence of TASP1 in fibroblasts, underexpression of HOX genes and a methylation profile intermediate between controls and Kabuki syndrome, which classifies SULEHS as a histone modification disorder [47]. A Turkish patient homozygous for c.404-2A>G with prolonged follow-up added cystic hygroma, increased nuchal translucency, coarctation of the aorta, pulmonary stenosis, pulmonary sequestration and aggressiveness, after a prior clinical diagnosis of Baraitser-Winter syndrome [48]. In 2026, the first Iranian case, with a homozygous missense variant of uncertain significance, brought to nine the number of patients with molecular confirmation; the review identifies as core features microcephaly, poor weight gain, thick, highly arched eyebrows with synophrys, hypertelorism, periorbital fullness, ear anomalies, recurrent respiratory infections, cardiovascular anomalies, developmental delay, happy demeanour and sialorrhoea [45]. The OMIM entry for SULEHS, from July 2020, rests on the 2019 series (four children aged 1 to 4 years, three from consanguineous families, variants 608270.0001 to 608270.0003) and adds details of the initial picture and the face: all four children required neonatal intensive care for hypotonia, respiratory failure or feeding difficulty; the three oldest began walking by 3 years, with poor motor skills, and had almost no expressive language, although some followed objects with their eyes and tried to communicate; microcephaly reached −5 standard deviations; the face combined excessive frontal hair, thick eyelids, a long smooth philtrum, a thin upper lip and low-set, prominent ears with an overfolded helix; hirsutism, preauricular tag, webbed neck, micrognathia with retrognathia and a wide mouth were less frequent, and there were seizures and sialorrhoea in two patients each; single palmar crease, polydactyly, clinodactyly, hydronephrosis, hearing loss and ophthalmological changes (hypermetropia, strabismus, amblyopia and optic disc pallor) completed the spectrum [22]. In that series, no variant had been studied functionally; loss of function was predicted, and confirmation in patient cells came with the 2022 work [22, 47].

The distinction from CAFDADD rests on inheritance (recessive, with consanguinity or a founder allele, versus de novo dominant), mechanism (biallelic loss of function versus dominant-negative missense), the face (thick eyebrows with synophrys versus blepharophimosis and ptosis) and systemic features (microcephaly, respiratory infections and happy demeanour in SULEHS; short neck, pectus carinatum, PDA and deafness in CAFDADD) [9, 45]. For counselling, the difference is decisive: 25% risk for each sibling in SULEHS, low risk for siblings of a de novo case in CAFDADD (section 8). An isolated case of a de novo heterozygous TASP1 variant in a child with severe craniofacial anomalies, dysgenesis of the anterior and posterior segments of the eye, immunodeficiency and macrocytic anaemia was published with a different mechanism, and is not part of the OMIM SULEHS phenotype [49].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no specific treatment nor any management guideline or consensus dedicated to CAFDADD; Xiao and colleagues write in 2026 that there is no curative treatment [6]. Management is multidisciplinary and addresses the malformations and functional disorders of each patient, relying on the recommendations of the authors of the series and on general guidelines for the manifestations (congenital heart disease, bicuspid aortopathy, sleep apnoea, neurodevelopment). Castilla-Vallmanya and colleagues point out that patients typically need educational support, that there is a risk of cervical stenosis and that older patients may benefit from surveillance for signs of premature ageing and for tumours, although it cannot be concluded that tumour risk is increased [9]. Kim and colleagues advocate regular ophthalmological, neurological and cardiological assessments, early developmental support, motor rehabilitation and attention to obstructive sleep apnoea [28]. Palma-Milla and colleagues proposed in 2024 oncological assessment and an evidence-based follow-up schedule; the schedule, also present in the preprint version of the study, was not accessible in full text, and the intervals presented here derive from the general guidelines cited and not from that schedule [17, 50].

7.2. Congenital heart disease in the newborn and child

Heart disease is the main cause of early complications, and echocardiography at diagnosis is the most important non-molecular investigation [8, 17]. The duct-dependent lesions described in the syndrome (pulmonary atresia, hypoplastic left heart, mitral atresia, severe coarctation) require, until corrective or palliative surgery, maintenance of ductal patency with alprostadil (prostaglandin E1) [13, 51]. The FDA (Food and Drug Administration) label of Prostin VR Pediatric® indicates the infusion as palliative, not definitive, therapy to temporarily maintain the patency of the ductus arteriosus in newborns whose survival depends on it. The initial dose is 0.05 to 0.1 µg/kg/min by continuous intravenous (IV) infusion into a large vein or through an umbilical artery catheter placed near the duct, always diluted; once a response is obtained, it is reduced progressively (0.1 → 0.05 → 0.025 → 0.01 µg/kg/min) to the lowest effective dose; if the response to 0.05 µg/kg/min is insufficient, it may be increased up to 0.4 µg/kg/min, although higher doses generally produce no greater effect [51]. Apnoea occurs in about 10 to 12% of newborns with heart disease, especially below 2 kg and in the first hour of infusion, so the medicine should be used only where assisted ventilation is immediately available; fever (about 14%), flushing, bradycardia, seizures (about 4%) and hypotension are frequent; infusions longer than 120 hours require monitoring for antral hyperplasia and gastric outlet obstruction [51]. Use is within the indication, which is defined by the physiology and not by the syndrome. In the European Union, paediatric alprostadil has national authorisations, without a European public assessment report; the Portuguese summary of product characteristics (SmPC) and the Brazilian package leaflet were not consulted.

PDA is the most frequent lesion, and most patients who underwent surgery had surgical closure (10 of 24 in the 2020 series, 6 of 8 in the 2024 cohort) [10]. Pharmacological closure with intravenous ibuprofen is authorised only in the preterm newborn: by the FDA, for NeoProfen® (ibuprofen lysine) in preterm infants between 500 and 1500 g with gestational age up to 32 weeks when usual treatment has failed; by the EMA (European Medicines Agency), for Pedea® (ibuprofen) in haemodynamically significant PDA in preterm infants of less than 34 weeks [52, 53]. In both labels, the course consists of three intravenous injections 24 hours apart, 10 mg/kg for the first and 5 mg/kg for the second and third, calculated by weight; the next dose is withheld if anuria or oliguria occurs (in the FDA label, urine output below 0.6 ml/kg/h); Pedea® is given as a short 15-minute infusion from 6 hours of life and allows a second course if the duct does not close 48 hours after the last dose or reopens, after which surgery may be needed; the FDA label also allows a second course, alternative pharmacological therapy or surgery if the duct does not close or reopens; no maximum dose is defined in the source beyond the three-dose regimen per course [52, 53]. Both labels contraindicate the medicine in congenital heart disease in which ductal patency is needed for pulmonary or systemic flow (pulmonary atresia, severe tetralogy of Fallot, severe coarctation), in serious infection, active bleeding, thrombocytopenia or coagulopathy, renal failure and necrotising enterocolitis, and the Pedea® SmPC requires prior echocardiography to exclude pulmonary hypertension and duct-dependent heart disease [52, 53]. In CAFDADD, this contraindication is relevant, because the syndrome includes duct-dependent lesions. In the term child with PDA, the labels do not apply; the sources consulted describe surgical correction, with no data on the choice between percutaneous and surgical techniques [9, 10].

The remaining lesions (ASD, VSD, valve disease, coarctation, double outlet right ventricle, univentricular physiology) follow the usual approach for each heart defect; the sources do not describe surgical results specific to the syndrome. The prolonged QT interval recorded in one patient and the conduction abnormalities mentioned by GeneGuidance warrant an electrocardiogram at the initial assessment [8, 13].

7.3. Bicuspid aortic valve and aortopathy

BAV was recorded in 2 of 7, 6 of 42 and 2 of 21 patients in the three cohorts, and the only adult with a detailed cardiovascular description had growth of the aortic root from 45 to 58 mm in two years [9, 10, 13, 28]. There are no specific recommendations for the aortopathy of CAFDADD; those for BAV apply. The 2022 American College of Cardiology and AHA (ACC/AHA) guideline on aortic disease recommends what the table summarises [46].

Source: 2022 ACC/AHA guideline on aortic disease [46]. Classes: 1, recommended; 2a, reasonable; 2b, may be considered. Levels: B-NR, non-randomised data; C-LD, limited data; C-EO, expert opinion.

Transposing these thresholds to CAFDADD requires caution. The guideline addresses BAV without hereditary aortic disease, and CAFDADD is not a recognised hereditary aortic disease; the rapid growth in the Korean case and the associated BAV lead to managing the adult patient at least as a carrier of BAV with dilatation [28, 46]. Echocardiography may be limited by pectus carinatum, as in that patient, which makes CT or MRI necessary [28, 46]. The Korean authors cited the surgical thresholds of the 2021 European valvular heart disease guideline (>55 mm in general, >50 mm in Marfan syndrome, >45 mm with risk factors or a genetic variant, >50 mm in BAV with risk factors or coarctation) [28]; that guideline has since been superseded by the 2025 European Society of Cardiology and European Association for Cardio-Thoracic Surgery (ESC/EACTS) guideline, and the ESC published in 2024 a guideline on peripheral arterial and aortic diseases [54]. The texts of these two European guidelines were not consulted, so the divergence between current European and North American thresholds was not ascertained.

7.4. Airway and obstructive sleep apnoea

The 2012 American Academy of Pediatrics (AAP) guideline on paediatric OSAS, written for uncomplicated OSAS and which considers syndromic patients high risk, recommends asking about snoring at every health surveillance visit, performing polysomnography when there is snoring with signs or symptoms of OSAS, considering adenotonsillectomy as first line if there is adenotonsillar hypertrophy, monitoring high-risk patients as inpatients after surgery, reassessing after surgery, using continuous positive airway pressure when surgery is not indicated or OSAS persists, promoting weight loss in overweight patients and allowing intranasal corticosteroids in mild OSAS [55]. In CAFDADD, micrognathia or retrognathia (13 of 42), the short neck and the vertebral and palatal anomalies create an anatomical substrate; the Korean case illustrates severe OSAS due to narrowing of the naso- and oropharynx with a retropositioned mandible, treated with continuous positive airway pressure, with repercussions on the right ventricle [9, 28].

7.5. Sleep disorders and melatonin

Sleep disorders are part of the spectrum, and autism spectrum disorder (ASD) affects 6 of 42 patients [9, 17]. After OSAS has been excluded and sleep hygiene measures have proved insufficient, prolonged-release (PR) melatonin (Slenyto®, 1 mg and 5 mg tablets) is authorised in the European Union for insomnia in children and adolescents aged 2 to 18 years with autism spectrum disorder and/or neurogenetic disorders with abnormal daytime melatonin secretion and/or night-time awakenings [56]. In a child with CAFDADD and autism spectrum disorder, use is within the indication; without autism, classification as a neurogenetic disorder with abnormal melatonin secretion has not been demonstrated, and use is an extrapolation. The initial dose is 2 mg once a day, 30 to 60 minutes before bedtime, with or after food; if the response is insufficient, it is increased to 5 mg, up to a maximum of 10 mg; the tablets are taken whole and may be mixed with yoghurt, orange juice or ice cream and swallowed immediately; the effect is assessed after at least 3 months and treatment is reassessed at least every 6 months; there are no data beyond 2 years of treatment and no relevant use below 2 years of age [56]. The most frequent adverse effects are somnolence, fatigue, mood swings, headache, irritability, aggressiveness and morning hangover; the medicine is not recommended in autoimmune disease or hepatic impairment, is metabolised by CYP1A and should be avoided with fluvoxamine, alcohol, hypnotics, thioridazine and imipramine; it contains lactose; the only contraindication is hypersensitivity [56]. In pregnancy it is preferable to avoid it, owing to lack of data, and in breastfeeding the decision weighs the benefit of breastfeeding [56]. In Portugal, the centrally authorised medicine is valid; registration in Brazil was not consulted.

7.6. Neurodevelopment, communication and education

Early developmental support, motor rehabilitation and learning support are part of the authors' recommendations [9, 28]. Expressive language is disproportionately affected, and many patients need augmentative and alternative communication [17]. Assessment for autism spectrum disorder, management of epilepsy according to seizure type and educational support complete the plan; the sources do not describe particular responses to antiseizure medication in the syndrome [9, 13]. Developmental regression, described in one patient, requires investigation [13].

7.7. Hearing, vision, skull, spine and other systems

Deafness, conductive, sensorineural or mixed, affects half of patients (21 of 42), which makes audiological assessment part of the initial assessment; the sources do not describe results of hearing aids or cochlear implants in the syndrome [9]. Ophthalmological assessment should look for ptosis with risk of amblyopia, strabismus, refractive errors, optic atrophy and congenital glaucoma [9, 13, 29]. Multisutural craniosynostosis, sinus pericranii and anomalies of the craniocervical junction fall within the neurosurgical remit; Accogli and colleagues discuss the management implications of these anomalies, in a text consulted only in abstract [25, 26]. Castilla-Vallmanya and colleagues point out the risk of cervical stenosis, and in the Korean adult craniocervical angulation with spinal cord compression was identified by cervical MRI [9, 28]; in the presence of signs of myelopathy, targeted imaging of the cervical spine is the indicated examination. The renal anomalies (10 of 42) and the pelvicalyceal dilatations with urinary tract infection described make renal assessment relevant [9, 37]. Feeding difficulties frequently required tube feeding in the first year, and short stature and endocrine manifestations warrant endocrinological assessment of growth [8, 9, 17].

7.8. Agents to avoid and perioperative context

Ibuprofen and other medicines that close the ductus arteriosus are contraindicated when the circulation depends on the duct [52, 53]. For melatonin, fluvoxamine and the other agents listed in the SmPC should be avoided [56]. The sources do not describe anaesthetic complications specific to the syndrome or specific anaesthetic recommendations. The documented findings (retrognathia and narrowing of the naso- and oropharynx, short neck, cervical stenosis and craniocervical angulation with spinal cord compression, heart disease, OSAS) are relevant to the pre-anaesthetic assessment, and OSAS in high-risk patients warrants inpatient monitoring after airway surgery [9, 28, 55].

7.9. Pregnancy and transition to adulthood

Affected women who have had children are documented, including a mother with a de novo variant and affected twins and a mosaic mother with PDA and intellectual disability [9, 15]. There are no data on obstetric complications in the syndrome. In the woman with BAV and a dilated aorta, the ACC/AHA recommends aortic imaging before pregnancy and prior surgery if the diameter reaches 5.0 cm [46]. Transition to adult care should transfer cardiological surveillance (aorta, residual valve disease, sequelae of surgery), hearing, ophthalmological, orthopaedic and sleep surveillance and incorporate attention to signs of premature ageing (hair loss, atherosclerosis, osteoporosis) and the clinical surveillance for tumours proposed by the authors, without a defined protocol [9, 28].

7.10. Dosage of supportive medicines

No guideline sets doses for CAFDADD. The doses below come from official labels and apply to the manifestations (duct-dependent heart disease, PDA in the preterm infant, insomnia), not to the syndrome.

7.11. Regulatory status

7.12. Trials and therapeutic evidence

A search of ClinicalTrials.gov on 28 October 2026 with the terms "TRAF7", "CAFDADD", "Suleiman-El-Hattab" and "TASP1" returned no registered study; absence of registration does not prove absence of research [20]. The available evidence is summarised in the table.

The Slenyto® trial did not include patients with CAFDADD; transposing the effect assumes that insomnia in the syndrome responds like that of the populations studied. The selumetinib studies are pathway validation experiments, with experimental doses in animals without clinical translation; the authors themselves warn that embryonic structural defects are unlikely to be reversed by postnatal pathway inhibition, that TRAF7 has other substrates and that the results do not constitute evidence for a therapeutic strategy [6]. There are no negative trials, suspensions or withdrawals to record for the syndrome.

7.13. Developments in the last 6 to 12 months

Between late 2025 and October 2026, the literature on CAFDADD brought one mechanistic study and two clinical reports. The study by Xiao and colleagues (Science Advances, 2026) proposed stabilisation of KRAS and NRAS with MEK–ERK hyperactivation as a dominant-negative mechanism, described the first knock-in mouse model of the recurrent variant and tested selumetinib in organoids and in the mouse (preclinical evidence) [6]. On the clinical side, a Japanese patient without developmental delay or intellectual disability (case report, 2025) and primary congenital glaucoma in a Spanish patient (case report, 2026) were published, both consulted only as title and metadata [11, 29]. In SULEHS, the first Iranian case (2026) was accompanied by a review of the nine confirmed patients [45]. On the regulatory side, there were no acts relating to the syndrome; the product information of Slenyto® was updated on 10 June 2026, and the earlier extension to attention deficit hyperactivity disorder (European Commission decision of 17 March 2025) does not change the indication applicable to insomnia with ASD or neurogenetic disorder [56].

7.14. Guidelines and divergences

There is no guideline specific to CAFDADD. The recommendations used come from the 2021 ACMG guideline on exome and genome sequencing [18], the 2018 AHA scientific statement on the genetics of congenital heart disease [42], the 2022 ACC/AHA guideline on aortic disease [46] and the 2012 AAP guideline on paediatric OSAS [55]. The equivalent European guidelines for aortopathy and valvular heart disease (ESC 2024; ESC/EACTS 2025) were not consulted, and divergences in surgical thresholds between societies were not ascertained [54]. The AAP guideline excludes from its main scope syndromic patients, whom it considers high risk [55].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

CAFDADD has autosomal dominant inheritance, and most cases result from de novo variants (36 of 45 in the 2020 series; 6 of 7 in the founding article) [9, 13]. For the parents of a child with a confirmed de novo variant, the recurrence risk is low but not zero, because of parental germline or somatic mosaicism: in the 2020 series, one case resulted from low-level maternal mosaicism [9], and in the African-American family the mother, with 33.89% variant allele in leucocytes and a phenotype of her own, transmitted the variant to her son [15]. The sources do not provide a numerical estimate of the empirical recurrence risk for siblings.

For an affected patient, the risk of transmission is 50% in each pregnancy, documented in the mother with a de novo variant and affected dizygotic twins and in the 43-year-old patient with two affected offspring [9, 10]. Expressivity varies within the same family (only one of the twins with heart disease; a mother with polydactyly and dysmorphic features that her son did not have), so it is not possible to predict severity, particularly cardiac severity, from the parent [15, 31]. When the parent is mosaic, the risk to offspring depends on the gonadal fraction, which cannot be measured, and the offspring who inherits the variant is constitutionally heterozygous, with a potentially more complete picture than the parent [15]. The incomplete penetrance proposed for inherited variants in non-syndromic heart disease is not established and should not be used as a basis for counselling [10, 30, 31].

8.2. Testing of relatives

The parents of a patient should be tested to confirm de novo occurrence; high-depth sequencing of blood can detect low-level mosaicism, as in the founding article, in which parental mosaicism was excluded at depths greater than 22,000 reads [13]. A parent with mild features (ptosis, PDA, learning difficulties) should be examined and tested, because they may be mosaic [15]. Siblings need testing only when a parent is a carrier or mosaic, or when they have compatible signs. The ACC/AHA recommends echocardiographic screening of first-degree relatives of a patient with BAV and aortic dilatation and considers it reasonable in BAV without dilatation [46].

8.3. Prenatal and preimplantation diagnosis

When the familial variant is known, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing make it possible to identify carrier embryos or fetuses. In pregnancies without a known familial variant, ultrasound may detect heart disease, cystic hygroma, single umbilical artery or growth restriction [13], and prenatal exome sequencing of chorionic villi has already allowed diagnosis after structural anomalies [27]. Malinowski and colleagues stress the importance of detailed ultrasound and access to prenatal exome sequencing for decisions about the pregnancy [27]. In a couple with a child affected by a de novo variant, targeted prenatal diagnosis makes it possible to exclude recurrence due to germline mosaicism.

8.4. Content of counselling

Counselling should explain the molecular diagnosis, the variability of expression (including the possibility of normal or near-normal cognitive development in some patients) [11, 17], the foreseeable surveillance needs, the recurrence risk in the specific scenario and the distinction between the germline variant and somatic tumour variants. A germline TRAF7 variant does not establish a predisposition to meningioma, and the tumour surveillance proposed by the authors is based on a small number of adults [8, 9]. The AHA stresses the need for counselling before and after genetic testing in congenital heart disease [42]. In asymptomatic minors, testing is warranted only when there are compatible signs or when the result changes surveillance (for example, echocardiography); testing for purely reproductive purposes is deferred until the person is old enough to decide.

8.5. Counselling in SULEHS

In Suleiman-El-Hattab syndrome, inheritance is autosomal recessive: the parents of an affected child are, as a rule, heterozygous carriers, with a 25% risk in each pregnancy; consanguinity and a founder deletion of exons 5 to 11 of TASP1 have been described in the United Arab Emirates [23, 45]. The distinction between the two entities therefore has direct consequences for the recurrence risk.

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the numbers measure

There is no population estimate of the prevalence or incidence of CAFDADD. Orphanet classifies the worldwide point prevalence as less than 1 per 1,000,000 and records 55 published cases or families, based on four publications, a number that is a bibliographic count at the date of annotation and not a prevalence [7]. Counts have grown with the use of exome sequencing: 7 patients in 2018 [13], 45 in 2020 [9], more than 50 published and 21 new in 2024 [10], 69 in the 2024 Spanish review [17] and 96 patients with 31 variants compiled in 2026 [6]; the Human Disease Genes page, updated in October 2026, mentions fewer than one hundred published cases [41]. These compilations may overlap, and none measures the frequency at birth.

The only relative frequency datum comes from the cohort of about 7700 undiagnosed exomes from Baylor College of Medicine, in which seven de novo TRAF7 variants were identified; the number measures enrichment in a population referred for exome sequencing, not the frequency in the general population [13]. In a Chinese series of 101 children with congenital heart disease, one patient had a pathogenic TRAF7 variant [43]. The p.(Arg655Gln) variant, in about one third of patients, owes its recurrence to the hypermutability of a CpG dinucleotide and not to a founder effect [6, 13].

9.2. Geographical distribution and ancestry

Published patients come mainly from the United States and Europe (France, Italy, Spain, Norway, the Netherlands, Poland and other countries of the international series), with cases in Australia, China, Japan and South Korea [9–11, 25, 26, 28, 36, 37]. In the United States, an African-American family with maternal mosaicism and a prenatal diagnosis in Maryland have been published [15, 27]. No founder effect or population with increased frequency has been described. The sources consulted do not include patients from Portugal or Brazil, which reflects the scope of the sources and does not demonstrate the absence of cases. The distribution reflects access to exome sequencing and participation in international consortia.

In SULEHS, the situation is different: nine patients are confirmed, with a founder TASP1 deletion in the United Arab Emirates and cases in Turkey and Iran [23, 45, 48].

9.3. Special populations

In adults, experience is limited to a few patients, up to 46 years of age, with signs of premature ageing and aortic root aneurysm described [9, 10, 28]. In women of reproductive age, vertical transmission is documented, and BAV with aortic dilatation requires assessment before pregnancy [9, 46]. In the preterm newborn with PDA, the indications and contraindications of intravenous ibuprofen described in section 7 apply [52, 53]. People with mosaicism may have an attenuated phenotype and go unnoticed until the diagnosis of an offspring [15].

9.4. Reference networks and patient associations

In Europe, the relevant European reference network is ERN ITHACA (rare malformation syndromes, intellectual disability and other neurodevelopmental disorders), one of the 24 networks, with a working group dedicated to neurodevelopmental disorders; La Paz University Hospital, in Madrid, a member of the network, took part in the Spanish series [17, 21]. The Human Disease Genes page on TRAF7 has versions for professionals and for parents (https://humandiseasegenes.nl/traf7/parents) [41]. No patient association dedicated to CAFDADD was found; generic resources for rare diseases and syndromes without a name exist.

10. Illustrative Clinical Case

10.1. Adult with late diagnosis and aortic root aneurysm

Kim and colleagues published in 2024 the first Korean case of CAFDADD [28]. The patient was a 36-year-old man, the first child of non-consanguineous parents, born at 38 weeks after an uneventful pregnancy and with normal growth at birth. Since birth he had generalised hypotonia, bilateral blindness and hearing impairment; the almost complete blindness, without light perception, was diagnosed at around 2 years, with optic atrophy and low-amplitude visual evoked potentials. Global development was delayed, and in adulthood the intelligence quotient was 75; he attended a school for children with disabilities and did not live independently. He had snored since childhood.

At 36 years, examination showed short stature (153.7 cm, below the 3rd centile), a short neck, pectus carinatum, a dorsal hump, redundant nuchal skin, oedematous eyelids with blepharophimosis, a broad nasal root, a high forehead, arachnodactyly and lower limb oedema; body mass index was 28 kg/m². Brain MRI showed diffuse cerebral atrophy and cranial bone thickening, and cervical MRI showed severe angulation of the craniocervical junction with spinal cord compression; there was also lumbar scoliosis, disc protrusion and cervical spondylosis. Two years earlier, a TTE with a poor acoustic window because of the pectus carinatum had shown an ejection fraction of 59% and an ascending aorta of 45 mm. Admitted for dyspnoea, he had an NT-proBNP of 248.10 pg/ml (reference 42.5–106.4) with normal troponin T and CK-MB; CT angiography revealed an aortic root aneurysm of about 58 mm at the sinus of Valsalva, BAV, aortic regurgitation and right ventricular dilatation without significant pulmonary hypertension. He underwent Bentall surgery, with a 21 mm prosthetic aortic valve, replacement of the ascending aorta and reimplantation of the coronary ostia.

After surgery, dyspnoea and nocturnal desaturations persisted. Facial CT and laryngoscopy showed narrowing from the nasopharynx to the oropharynx due to a retropositioned mandible, and polysomnography revealed severe OSAS, with an apnoea–hypopnoea index of 88 per hour and minimum saturation of 74%. Continuous positive airway pressure relieved the symptoms; on postoperative day 32, the right ventricle remained dilated, which the authors attributed to OSAS, aggravated by the vertebral anomaly and the short neck.

Genetic investigation began with karyotype and microarray, which were normal, with suspicion of a connective tissue disorder or RASopathy. A clinical exome (panel of about 7000 genes) identified NM_032271.3:c.1964G>A p.(Arg655Gln) in the heterozygous state, confirmed by Sanger and absent in the parents and brother, classified as pathogenic (PS2, PM1, PM2, PP1, PP2, PP3) [28]. The authors discussed Loeys-Dietz syndrome as the closest differential and recommended regular ophthalmological, neurological and cardiological assessments. Figure 1 of the article brings together the pedigree, the phenotype, the visual evoked potentials and the brain and cervical MRI, and Figure 2 the CT angiography and echocardiography, according to the article's legends (https://pmc.ncbi.nlm.nih.gov/articles/PMC11011995/) [28].

The case shows three aspects with practical consequences: the diagnosis may come only in adulthood, after decades of typical manifestations; BAV may progress to a root aneurysm with growth of 13 mm in two years, and pectus carinatum limits TTE; and the narrow upper airway exposes the patient to severe OSAS with cardiac repercussions. The aortic surveillance that would have been indicated by the ACC/AHA guideline for a 45 mm aorta (lifelong imaging with repetition at 6 to 12 months to measure the growth rate) is not described in the report, which does not allow it to be known whether the two-year interval was a clinical choice [28, 46].

10.2. Infant with blepharophimosis and suspected BPES

Paprocka and colleagues described a Polish boy born at 41 weeks, weighing 3100 g, with a head circumference of 32 cm and a short two-vessel cord [37]. At 2 months he had oedematous eyelids with fissures opening 2 to 3 mm, small deep-set eyes, ophthalmoplegia, a broad nose with an upturned tip, retrognathia, asymmetric pinnae, head circumference below the 3rd centile, a narrow chest with widely spaced nipples, patent foramen ovale or type II ASD with PDA, and left pelvicalyceal dilatation with urinary tract infection. Repetitive stimulation and acetylcholine receptor antibodies excluded myasthenia. Microarray was normal, and the exome, requested for suspected BPES, identified NM_032271.3:c.1708C>G p.(His570Asp) de novo, absent from gnomAD and from more than 3500 Polish exomes, classified as likely pathogenic. The case illustrates the misleading initial direction to which blepharophimosis can lead and the importance of heart disease as a discriminating sign [37].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

There are no survival or prospective natural history studies. Early prognosis depends mainly on the heart disease, which may be severe and become complicated early; the founding article includes newborns with univentricular physiology, double outlet right ventricle and cardiorespiratory arrest [13, 17]. The series include patients up to 46 years of age [10], but mortality has not been quantified. Functional prognosis is variable: all patients in the 2020 series had some developmental delay and 23 of 42 had recorded intellectual disability, while some patients reach normal development [9, 11, 17]. In adulthood, the reports describe short stature, sensory deficits, degenerative joint and spinal changes, aortic root aneurysm and signs of premature ageing, in a number of patients too small to estimate frequencies [9, 13, 28]. The germline tumour risk is not established [6, 9].

11.2. Initial assessment and surveillance

The follow-up schedule proposed by Palma-Milla and colleagues was not accessible; the table brings together what the sources consulted support and indicates, where applicable, that the interval is not defined [17].

11.3. Long-term follow-up

In adulthood, follow-up should maintain aortic imaging in carriers of BAV, surveillance of operated cardiac sequelae, attention to the airway and sleep, orthopaedic and spinal assessment and the clinical surveillance for signs of premature ageing and tumours proposed by the authors, without a validated protocol [9, 28, 46]. Clinical assessment of focal neurological symptoms in the adult should consider the possibility of meningioma, described in a 43-year-old patient, although there is no indication for systematic imaging screening [6, 9].

12. Summary and Final Considerations

Cardiac, facial and digital anomalies with developmental delay (CAFDADD; OMIM 618164; ORPHA:592570) is an autosomal dominant disorder, almost always de novo, caused by germline missense variants in TRAF7, concentrated in the WD40 domain and, in smaller numbers, in the coiled-coil, with p.(Arg655Gln) in about one third of patients. The designation "Suleiman-El-Hattab syndrome", sometimes applied to this syndrome, corresponds to another entity, autosomal recessive, caused by TASP1 (OMIM 618950), which enters only into the differential diagnosis.

The mechanism is not haploinsufficiency: the variants act through a dominant-negative effect on the normal protein, and the most recent model attributes to them the stabilisation of KRAS and NRAS with hyperactivation of the MEK–ERK pathway, alongside effects on cilia and the neural crest. Somatic TRAF7 variants in meningiomas and other tumours occupy different positions and have no germline implication.

The clinical picture combines developmental delay with particularly affected expressive language, blepharophimosis and ptosis, a short neck with pectus carinatum, digital anomalies, congenital heart disease dominated by PDA, deafness and, less frequently, craniosynostosis, anomalies of the craniocervical junction, renal anomalies and growth deficiency. Adults may develop aortic root aneurysm associated with BAV, OSAS and signs of premature ageing, and the cognitive spectrum includes patients with normal development.

The diagnosis is made by exome sequencing, preferably trio, or by a panel including TRAF7; microarray does not detect the causal variants, and mosaicism is a real limit of the tests. There is no specific treatment: management rests on correction of the heart disease (with alprostadil in duct-dependent lesions), aortic surveillance according to the rules for BAV, auditory, visual and developmental rehabilitation, augmentative communication, treatment of OSAS and sleep disorders and attention to the cervical spine. MEK1/2 inhibition with selumetinib remains in the preclinical domain. The recurrence risk is low for the parents of a de novo case, with the caveat of parental mosaicism, and 50% for the offspring of a patient, with unpredictable expressivity. The main gaps are the absence of natural history studies, survival data and a validated follow-up schedule, and the quantification of aortic and tumour risk in the adult.

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