Catel-Manzke Syndrome (TGDS) and the KYNU Spectrum

Robin sequence with index finger hyperphalangy: TGDS-associated Catel-Manzke syndrome (13q32.1), Catel-Manzke-like phenotype due to kynureninase deficiency (KYNU, 2q22.2) and other differential diagnoses with an accessory ossicle of the second finger

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Founding descriptions

Catel-Manzke syndrome owes its name to two German observations five years apart. Catel described in 1961, in a textbook of paediatric differential diagnosis, a child with the Robin anomaly and a peculiar deviation of the index fingers, and Manzke re-examined the same patient in 1966 and demonstrated radiologically the cause of the deviation: an accessory bone interposed between the second metacarpal and the corresponding proximal phalanx, which he called symmetrical hyperphalangy of the second finger [1–3]. This original patient was followed into adulthood: re-examined at 27 and 47 years, he had no relevant disability and ran his own business, and he was 52 years old with two healthy children when his variant was identified in 2014 [3, 11, 22]. The name "palatodigital syndrome, Catel-Manzke type" became established in the following decades, and Manzke later proposed replacing it with "micrognathia-digital syndrome", because some patients do not have a cleft palate; the radiological sign of the index finger became known as Manzke dysostosis [3, 4].

Isolated reports from the 1980s and 1990s, among them those of Sundaram and colleagues (1982), Dignan and colleagues (1986) and Kant and colleagues (1998), consolidated the phenotype; the 2008 review added heart disease, joint hypermobility, chest deformities, short halluces and fifth finger clinodactyly to the description [1, 4, 23]. Gewitz and colleagues (1978) and Stevenson and colleagues (1980) suggested a familial basis, the latter in a family with several affected members in successive generations, and Brude (1984) proposed X-linked recessive inheritance; the syndrome was at one time assigned OMIM number 302380, which still appears in the 2008 review and in the 2014 article [3, 11, 22]. The first female patients, two sisters, were described by Dignan and colleagues in 1986, in a family in which a subsequent pregnancy ended with a stillborn fetus at 26 weeks with cleft palate, index finger anomalies and heart disease [11]. The description of two affected sisters in one family, two brothers in another and parental consanguinity in a third led to the proposal of autosomal recessive inheritance, reinforced in 2011 by a Turkish infant of consanguineous parents with a possibly affected sibling [3, 24].

1.2. Historical clinical classification

In 2008, Manzke and colleagues critically reviewed the literature and divided the published cases into four groups: 23 cases of the typical form, with Robin anomaly and bilateral index finger hyperphalangy; six cases of the extended form, with more than two accessory bones in the hand; two patients with unilateral index finger hyperphalangy and clinodactyly; and two patients with isolated Manzke dysostosis, without Robin anomaly [22]. In 2014, Ehmke's group counted 26 individuals from 24 families with the typical form and ten atypical cases (extended phenotype or unilateral hyperphalangy), in addition to the two cases of Manzke dysostosis without Robin sequence [3]. Puri and Phadke (2003) proposed the term "mandibulo-digital syndrome" for a boy with retrognathia and index finger anomalies without cleft or heart disease, and Manzke and colleagues preferred "micrognathia-digital syndrome" [11]. The expression "Catel-Manzke-like" came to designate patients lacking one of the two cardinal signs or with additional hand malformations [4].

1.3. Molecular discovery and reclassification

Exome sequencing of seven unrelated individuals with the typical form identified biallelic variants in TGDS in all of them in 2014, with six different variants and one recurrent variant, c.298G>T p.(Ala100Ser), shared on a 50 kb haplotype, suggesting a European founder effect [3]. OMIM then assigned the syndrome number 616145 and the gene number 616146 [9, 25]. Subsequent reports broadened the TGDS-associated spectrum: an infant with Robin sequence without cleft and severe respiratory complications (2015), a fetus with additional malformations of the middle fingers and halluces (2017), two individuals with TGDS variants without radiological hyperphalangy and with disproportionate short stature (2020) and a patient with Robin sequence without Manzke dysostosis (2020) [4, 18, 25, 26]. In the light of these cases, Boschann and colleagues questioned the usefulness of the division between typical and atypical forms and proposed a molecular classification, "TGDS-associated Catel-Manzke syndrome" [4].

In parallel, it was shown that the clinical phenotype has other causes. In 2012, homozygous loss-of-function variants in IMPAD1 (now BPNT2) were found in two patients classified as Catel-Manzke-like, and in 2015 a patient with bilateral hyperphalangy, heart disease and vertebral anomalies had no variants in the known genes after exome sequencing [27, 28]. In 2020, three patients with a clinical diagnosis of Catel-Manzke, heart disease, short stature and developmental delay had biallelic variants in KYNU, the kynureninase gene, and in 2021 a child with a phenotype overlapping Catel-Manzke syndrome and VCRL syndrome had a homozygous deletion of KYNU exon 5 due to maternal isodisomy of chromosome 2 [6, 7]. In 2025, the description of two infants with kynureninase deficiency followed in the Netherlands included the first report of treatment with nicotinamide and pyridoxine [19]. These cases link index finger hyperphalangy to the de novo NAD synthesis pathway from tryptophan, whose congenital deficiency had been described in 2017 [8, 21].

The latest milestone is biochemical. In 2025, Jacobs and colleagues showed that TGDS produces UDP-4-keto-6-deoxyglucose (UDP, uridine diphosphate), a metabolite that reactivates UDP-xylose synthase (UXS1) when the latter becomes trapped with the reduced form of the cofactor (NADH) in the active site, and that lack of this metabolite impairs the synthesis of glycans required for skeletal development [29]. A zebrafish model published in the same period reproduces craniofacial cartilage changes with reduced sulphated glycosaminoglycans [30].

1.4. Definitions and scope of the article

TGDS-associated Catel-Manzke syndrome is defined by the presence of biallelic pathogenic or likely pathogenic variants in TGDS in a patient with a compatible phenotype, which almost always includes the Robin sequence and, in most cases, Manzke dysostosis; neither cleft palate nor hyperphalangy is mandatory [4, 18, 29]. The Robin sequence is defined by the triad of micrognathia, glossoptosis and upper airway obstruction, with cleft palate in most patients [20, 31]. Manzke dysostosis is the presence of an accessory ossification centre between the base of the proximal phalanx and the second metacarpal, which causes radial deviation at the metacarpophalangeal joint, ulnar clinodactyly and shortening of the index finger, and which fuses with the proximal phalanx with age [1, 4].

The KYNU-related Catel-Manzke-like phenotype corresponds to patients with index finger hyperphalangy and biallelic KYNU variants, which GeneReviews includes in congenital NAD deficiency disorder together with HAAO and NADSYN1 [6, 8]. CNDD and the VACTERL association, the Robin sequence and the brachydactylies enter the differential diagnosis; this article describes what is specific to Catel-Manzke syndrome, the KYNU-related form where it overlaps with it, and the differential diagnosis of index finger hyperphalangies.

2. Molecular Genetics and Pathophysiology

2.1. The TGDS gene and its protein

The TGDS gene is located at 13q32.1 and encodes TDP-glucose 4,6-dehydratase, also called dTDP-D-glucose 4,6-dehydratase or growth-inhibiting protein 21 (aliases TDPGD and SDR2E1) [2, 9]. The protein has 350 amino acids and belongs to the short-chain dehydrogenase/reductase (SDR) family, with a Rossmann fold formed by a central β-sheet flanked by α-helices, and has predicted NAD(P)-binding and substrate-binding domains, an active site and a homodimerisation interface [3]. It shares 35% identity with the Escherichia coli orthologue, which converts dTDP-glucose into dTDP-4-oxo-6-deoxy-D-glucose in the rhamnose pathway, a bacterial cell wall sugar that does not exist in human cells; for this reason, the function of the human enzyme remained unknown until 2025 [3, 29]. The closest human paralogue is UXS1 (UDP-glucuronate decarboxylase 1), with 25%–27% identity, a Golgi enzyme that produces UDP-xylose, the sugar that initiates the tetrasaccharide linker attaching glycosaminoglycans (GAG) to proteoglycans and which is required for α-dystroglycan glycosylation; Uxs1-null mice die in utero and UXS1 deficiency shortens the long bones in mice and humans [3, 29].

2.2. Mechanism: a UXS1 rescue metabolite

UXS1 uses NAD+ as a cofactor that remains bound in the active site and alternates between the oxidised and reduced forms during the conversion of UDP-glucuronate into UDP-xylose. Occasionally, the reaction intermediate (UDP-4-ketoxylose) escapes from the active site and the enzyme becomes inactive with NADH bound; exchange of NADH for NAD+ would restore activity, but NAD+ is scarce in the endoplasmic reticulum, and probably in the Golgi, in cell types in which hexose-6-phosphate dehydrogenase (H6PD) consumes NAD+ [29]. TGDS produces small amounts of UDP-4-keto-6-deoxyglucose, a molecule that mimics the UXS1 intermediate, enters the blocked active site, is converted into UDP-6-deoxyglucose and regenerates NAD+ within the catalytic pocket itself, completing the cycle and reactivating the enzyme; the authors call it an "enzyme rescue metabolite" [9, 29]. Inactivation of H6PD makes TGDS dispensable for maintaining UXS1 activity, and all vertebrates have H6PD, UXS1 and TGDS, whereas insects have a UXS1 orthologue without H6PD or TGDS [29].

The functional consequences were demonstrated at several levels. In TGDS-deficient cell lines, UDP-xylose decreases markedly, heparan sulphate production falls and α-dystroglycan glycosylation (the laminin-binding matriglycan) is greatly reduced; these defects are reversed by re-expression of human TGDS, by expression of the bacterial enzyme ArnA, which produces similar 4-keto sugars, or by overexpression of UXS1 [29]. In fibroblasts from five individuals with Catel-Manzke syndrome and biallelic TGDS variants, compared with three controls, UDP-6-deoxyhexose (a product derived from the TGDS metabolite) was more than 80% below control levels in all patients, whereas UDP-xylose and UDP-glucuronate did not differ systematically, a result the authors attribute to cell-type-specific dependence on TGDS [29]. All variants tested significantly reduced the activity of the recombinant enzyme at saturating substrate concentration, without a change in the Michaelis constant in the variants with residual activity, and only NM_014305.4:c.714_716del p.(Val239del) reduced the amount of protein; residues Val239, Ala100 and Thr102 line the catalytic pocket, whereas Glu90 and Glu322 are peripheral [29].

The mechanism explains the clinical similarity with disorders of proteoglycan synthesis and sulphation. Saudubray includes TGDS in the table of GAG synthesis defects, alongside CANT1 (Desbuquois dysplasia type 1) and XYLT1 (formerly Desbuquois type 2), and the hyperphalangies associated with CANT1, IMPAD1/gPAPP and CHSY1 result from defects in the same pathway [3, 6, 32]. Bone Dysplasias proposes, on the basis of experimental models, that proteoglycan synthesis genes regulate the timing of chondrocyte maturation through a matrix feedback loop, which would explain the accelerated maturation and short stature of this group [33]. There is no clinical assay of TGDS activity and no clinical measurement of its metabolite [9].

2.3. Animal models

Complete inactivation of Tgds in the mouse is lethal early in embryogenesis. Compound heterozygous TgdsA100S/− mice, carrying the recurrent human variant p.Ala100Ser (murine model; human equivalent NM_014305.4 p.(Ala100Ser)) and a null allele, show at embryonic day 18.5 (E18.5; 11 controls and 9 mutants) a mild but significant reduction in the length of the skull, mandible and nasal bone, without cleft palate, and mild shortening of the long bones of all four limbs; digit morphology is normal [29]. In the organs of 8-month-old mice, UDP-4-keto-6-deoxyglucose is more than 80% below normal in brain, liver and kidney, with less UDP-xylose and more UDP-glucuronate, changes smaller than in null cell lines [29]. In zebrafish, recombinant Tgds has UDP-D-glucose 4,6-dehydratase activity (EC 4.2.1.76), syndrome-associated variants at conserved residues reduce enzyme activity and stability, and F0 knockout by CRISPR/Cas9 causes developmental defects, mainly craniofacial cartilage changes with fewer sulphated GAG [30]. These models reproduce the micrognathia and long bone shortening, but not the hyperphalangy.

2.4. TGDS variant spectrum

The variants described up to 2020 were mostly missense, and no patient had two null alleles, which led the authors to interpret them as hypomorphic alleles and partial loss of function as the mechanism [3]. The 2025 cohort added an in-frame deletion, NM_014305.4:c.714_716del p.(Val239del) (in ClinVar, NM_014305.4:c.711_716TGT[1], VCV004071468, pathogenic, one submitter) [29, 34], and a variant that abolishes the exon 6 splice acceptor, with a transcript lacking that exon demonstrated by reverse transcription followed by polymerase chain reaction (RT-PCR) [29]. The table brings together the variants whose notation was confirmed in VariantValidator.

The notation of all variants in the table was validated in VariantValidator on 31 October 2026, and the GRCh37 coordinates match those published [4, 10]. In Table 1 of the article by Boschann and colleagues, the recurrent variant appears written as "c.298G>A" in several columns; the text of the same article, the genomic coordinate and the protein consequence (serine) confirm c.298G>T [4, 10]. In silico predictors diverged for the variants of the original series: MutationTaster classified all as disease-causing, SIFT considered p.Phe98Leu and p.Tyr234His tolerated and PolyPhen-2 considered p.Phe98Leu benign, divergences that the authors attributed to different alignments [3].

2.5. The c.298G>T founder variant

Haplotyping of patients carrying c.298G>T, with ten informative markers, reconstructed a 50 kb haplotype shared by all of them, indicating a common origin [3]. The known carriers had German, French, Dutch, Czech and British/South American ancestry, and in the eight patients with TGDS variants known in 2015 the variant accounted for 68.75% of alleles [25]. In 2014, the variant had been observed in heterozygosity in 9 of 4300 Europeans in the Exome Sequencing Project and in 40 of 61,377 individuals in ExAC, without homozygotes among controls; assuming a carrier frequency of 0.002 in Europe, the authors estimated one homozygote per million people, a value consistent with the estimated clinical prevalence [3]. In gnomAD v4.1, the variant has an allele frequency of 0.0806% in exomes (1139 of 1,413,718 alleles) and of 0.100% in non-Finnish Europeans (1101 of 1,096,926), with rare occurrences in Africans (5 of 30,078), Ashkenazi Jews (4 of 24,674) and Latin Americans (1 of 31,392) and none in East Asians; the exomes include one European homozygote, with no phenotypic information available [36].

2.6. Genotype–phenotype correlation, penetrance and expressivity

There is no established genotype–phenotype correlation. The same c.700T>C variant causes typical hyperphalangy in one patient and is present, in homozygosity or combined with c.298G>T, in two individuals without radiological hyperphalangy [4]. Homozygosity for c.298G>T was described in the original patient of Catel and Manzke, with a favourable course up to 52 years, and in the infant with the most severe respiratory complications of the series [3, 25]. Expressivity is variable within the same variant and between families, and forms without cleft, without hyperphalangy or with involvement of the middle fingers and halluces belong to the same spectrum [4, 18, 26]. Heterozygotes are healthy: the parents of patients and the two children of the original patient have no signs of the syndrome [3, 25].

2.7. KYNU and the de novo NAD synthesis pathway

NAD+ is formed by three pathways: de novo synthesis from tryptophan via the kynurenine pathway, the Preiss-Handler pathway from nicotinic acid, and the salvage pathway from nicotinamide and its derivatives (nicotinamide mononucleotide and nicotinamide riboside) [8]. Kynureninase, encoded by KYNU (2q22.2), is a pyridoxal 5'-phosphate-dependent enzyme that cleaves L-kynurenine and L-3-hydroxykynurenine into anthranilic and 3-hydroxyanthranilic acid, with a preference for the hydroxylated substrate [37]. Loss of its activity blocks the de novo pathway, causes accumulation of 3-hydroxykynurenine, kynurenine and xanthurenic acid and reduces the distal metabolites (3-hydroxyanthranilate, picolinate and quinolinate) and circulating NAD; embryonic NAD deficiency is the proposed mechanism for the malformations [6, 8, 21]. In 2017, Shi and colleagues described loss-of-function variants in HAAO or KYNU in four patients with cardiac, vertebral and renal malformations, with reduced circulating NAD, and showed that Haao- or Kynu-null mouse embryos developed similar defects, which were prevented when NAD deficiency was avoided during gestation [21].

The three KYNU variants of the patients with a Catel-Manzke-like phenotype reported in 2020 are normalised on the MANE transcript as NM_003937.3:c.1282C>T, NP_003928.1:p.(Arg428Trp) (NC_000002.12:g.143042056C>T), combined with an 85 kb maternal deletion spanning exons 1 to 8 of 14; c.989G>A, p.(Arg330Gln) (g.143033269G>A), in homozygosity; and c.326G>C, p.(Trp109Ser) (g.142927694G>C), in homozygosity [6, 10]. They were rare in gnomAD at the time (18, 1 and 3 heterozygotes, without homozygotes) and affect conserved residues in secondary structure elements of the enzyme [6]. The 2021 case has a homozygous 863 bp deletion that removes exon 5 (62 bp), with a predicted frameshift, resulting from maternal isodisomy of chromosome 2 [7].

Ehmke and colleagues noted that their three patients had at least one missense allele, whereas Shi's four patients had truncating variants, and suggested a possible genotype–phenotype correlation for hyperphalangy [6]. The review by Schüle and colleagues, with more cases, found no more severe phenotype in carriers of presumed null alleles than in carriers of missense alleles, and GeneReviews recognises neither genotype–phenotype correlations nor phenotypic differences between HAAO, KYNU and NADSYN1 [7, 8]. The 2020 authors also proposed a mechanistic bridge: TGDS and UXS1 are NAD+-dependent enzymes expressed in chondrocytes, so NAD deficiency could compromise the same glycan pathway [6].

2.8. Allelic disorders and nomenclature of the KYNU-related forms

Biallelic KYNU variants with residual activity cause hydroxykynureninuria (xanthurenic aciduria; OMIM 236800): in 2007, a boy who presented at 9 days with jaundice and vomiting and had xanthurenic acid on metabolic screening was homozygous for p.Thr198Ala and developed normally up to 6 years; his brother, also homozygous, was healthy with the same excretion; a heterozygous sibling had a mild increase in xanthurenic acid [14, 38]. This variant retains 64% activity in vitro [6]. Earlier biochemical descriptions, without molecular confirmation, included a child with massive excretion of kynurenine, 3-hydroxykynurenine and xanthurenic acid (1964), two siblings of first-cousin parents with intellectual disability whose excretion was temporarily corrected by high doses of vitamin B6 and whose hepatic kynureninase activity increased with pyridoxal phosphate (1967), and a consanguineous Algerian family with hypertonia, psychomotor delay, congenital deafness, non-progressive encephalopathy with exacerbations and renal tubular dysfunction (1996) [14]. GeneReviews considers it difficult to define the effects of this form beyond the urine, because the cases come from consanguineous families with possible other recessive diseases, and OMIM marks the relationship as provisional, with a single molecularly characterised family [8, 14]. The current interpretation is that of a continuum: mild blocks cause only xanthurenic aciduria and severe blocks, with less NAD+ available during organogenesis, cause malformations [6, 7]. As to nomenclature, the KYNU-related form corresponds to VCRL2 (OMIM 617661) and the HAAO-related form to VCRL1 (OMIM 617660); the 2021 article refers to its KYNU case as "VCRL1", an inconsistency in the source [6–8]. For TGDS, OMIM lists no phenotype other than Catel-Manzke syndrome, and the UXS1 entry has no associated human phenotype [12, 39]. In 2025, two novel KYNU variants in compound heterozygosity, NM_003937.3:c.256dup p.(Tyr86LeufsTer3) (maternal, pathogenic by American College of Medical Genetics and Genomics, ACMG, criteria) and c.1301G>A p.(Arg434Gln) (paternal, likely pathogenic), were described in a Dutch infant, and homozygosity for c.989G>A p.(Arg330Gln), previously described in a Turkish female patient, in an Afghan infant of consanguineous parents; the heterozygous parents had normal urinary and plasma metabolites [10, 19].

3. Clinical Spectrum and Manifestations by Organ System

3.1. Frequency sources and their limitations

There are two types of frequency data. Smith's Recognizable Patterns of Human Malformation presents percentages derived from the clinical literature preceding gene identification, without an explicit denominator, and Bone Dysplasias describes the major findings without frequencies [1, 2]. The 2008 review, cited by OMIM, estimated that about 70% of children had other severe congenital anomalies, such as heart defects, clubfoot, knee dislocation and joint laxity, in a clinical series without molecular confirmation [11]. Data with molecular confirmation come from small series: the table by Boschann and colleagues brings together the 11 individuals with TGDS variants described up to 2020 (seven from 2014, one from 2015, a fetus from 2017 and two from 2020), and the cohort of Jacobs and colleagues (2025) adds five individuals from Berlin and Paris, one of them already included in the 2014 series [4, 29]. The following frequencies should be read as proportions in case series with ascertainment bias, not as population estimates.

Sources: Smith [2]; molecular series [4]. In the molecular series, the 11 individuals were four males and seven females, of Dutch (three), German (three), Cameroonian, British/South American, French, German/Czech and Russian (fetus) origin, and none had consanguineous parents [4].

3.2. Craniofacial region and airway

The Robin sequence is the most constant feature: it was present in the 11 individuals with molecular confirmation compiled in 2020 and in all TGDS patients reviewed in 2021 [4, 7]. In the 2014 series, six of the seven patients had a cleft palate (U-shaped in four, V-shaped in one, type unspecified in another) and the seventh had a high palate with a bifid uvula [3]. The 2015 infant had a high, narrow palate with a small groove of the posterior soft palate, without a cleft, and ankyloglossia [25]. Bone Dysplasias mentions micrognathia with antegonial notching on radiography and mild micrognathia in a subgroup, and in the 2025 cohort tomography of one individual showed asymmetric micrognathia [1, 29]. Airway obstruction is the main cause of neonatal morbidity: the patient of Cameroonian origin required intubation and ventilation at birth and still had a tracheostomy at 18 months, and the 2015 infant had severe pharyngomalacia and laryngomalacia, mixed sleep apnoea, supraglottoplasty and tracheostomy at 7 months with nocturnal ventilation [3, 25]. Pharyngo/laryngomalacia, pharyngeal dysphagia, nasolacrimal duct obstruction, proptosis, facial paresis, a narrow tubular nose, cleft lip and a short neck are among the occasional manifestations [2].

The face has subtle features: thin or arched eyebrows, mild hypertelorism, upslanting palpebral fissures, proptosis, full cheeks, narrow nostrils, a long columella, a small mouth and low-set, posteriorly rotated ears or ears with dysplastic helices [2–4]. It does not constitute a recognisable gestalt without the hand signs.

3.3. Hands and feet

Manzke dysostosis manifests clinically as a crooked index finger, with radial deviation at the metacarpophalangeal joint and ulnar deviation at the proximal interphalangeal joint, that is, ulnar clinodactyly with shortening; there may be fifth finger clinodactyly and, rarely, ulnar deviation of the middle finger [1, 4]. On radiography, an accessory ossicle at the base of the abnormal proximal phalanx, triangular or "angel-shaped", is inserted between the second metacarpal and the proximal phalanx; the middle phalanx and the metacarpal of the index finger may be mildly hypoplastic and the epiphysis of the proximal phalanx of the middle finger may be deformed [1]. With age, the ossicle fuses with the proximal phalanx: in a 28-year-old woman, the right hand retained the triangular bone and the left already showed fusion [2, 3]. The finding is almost always bilateral, but the 2008 review included two unilateral cases, and an additional pin-shaped ossification centre was described in the left hand of a female infant [3, 22].

The digital spectrum is broader than the classic dysostosis. The 2017 fetus had deviation and clinodactyly of the index and middle fingers, with hypoplasia and V-shaped displacement of the second and third proximal phalanges, and hypoplasia of the first metatarsals and the phalanges of the halluces, but no visible hyperphalangy at 22 weeks [4, 26]. The two individuals reported in 2020 had mild radial deviation and clinodactyly of the index fingers with serial radiographs showing neither an ossicle nor shortening of the proximal phalanx, and another 2020 patient had Robin sequence without Manzke dysostosis [4, 18]. In the 2025 cohort, only one of five individuals had the ossicle; the others had fifth finger clinodactyly and one of them clinodactyly of the second to fourth fingers with distally widened metacarpals, and the authors describe Manzke dysostosis as a variable feature [29]. Brachymetacarpia, camptodactyly, adducted thumbs, short toes, a hypoplastic hallux, clubfoot and a broad foot complete the distal anomalies described [2, 3].

3.4. Growth

Postnatal growth deficiency is common, but it has two components. In infants with severe airway obstruction and dysphagia, the weight deficit is secondary: the 2015 infant had a weight z-score of −8.22 at 2 months and recovered to −1.22 at 12 months after gastrostomy and tracheostomy [25]. Bone Dysplasias notes that, once the neonatal period and early childhood are over, some patients achieve normal growth [1]. There is, however, an intrinsic short stature: six of nine individuals with molecular confirmation had short stature, and the two individuals without hyperphalangy had disproportionate short stature, with a height of −4.4 standard deviations (SD) and a sitting height/height ratio of +4.6 SD at 10–13 years in a girl whose familial target height was 169.7 cm, and a height of −2.7 SD with a ratio of +3.8 SD at 15 years in a boy; in both, the short femur was already visible on prenatal ultrasound [4]. Mild shortening of the long bones was described in 4 of the 11 individuals, in the 24-week fetus of the 2025 cohort and in the murine model [4, 29]. Smith includes prenatal growth restriction among the occasional findings [2].

3.5. Heart

Congenital heart disease occurs in a minority of patients with molecular confirmation (4/11) and is mostly simple: ventricular septal defects, one with spontaneous closure, and a small foramen ovale and ductus arteriosus that closed by 6 months [3, 4, 25]. The earlier clinical series mentions mainly septal defects, overriding aorta, coarctation of the aorta, dextrocardia and patent ductus arteriosus, and the 2017 fetus had severe heart disease [2, 26]. Bone Dysplasias includes heart disease among the factors that, together with airway obstruction, explain the initial growth delay [1]. Complex heart defects, such as hypoplastic left heart or tetralogy of Fallot, point towards the KYNU-related form [6].

3.6. Axial skeleton and large joints

Orthopaedic complications appear in childhood and adolescence. One female patient had Perthes disease of the right hip at 9 years and of the left at around 13, with incomplete recovery and leg length discrepancy, subluxation of both knees and hypermobile elbows; another required bilateral osteotomy for genu valgum; a third had bilateral hip dysplasia operated on with femoral osteotomy at 9 years [3, 4]. Smith recommends orthopaedic follow-up for Perthes disease, genu valgum and joint hypermobility [2]. Scoliosis, pectus excavatum progressing in the first year, vertebral and rib anomalies and anterior "beaking" of L2 and L3 have been described [2–4, 25]. Generalised joint laxity is one of the features that Bone Dysplasias uses to distinguish Desbuquois dysplasia [1]; the same book, in the entries for Desbuquois dysplasia and XYLT1 deficiency, states that laxity, short stature and metaphyseal changes had not been described in Catel-Manzke syndrome, a statement that subsequent molecular data correct for laxity and short stature [4, 33, 40].

3.7. Neurodevelopment, hearing and other systems

The great majority of patients with Catel-Manzke syndrome have normal intelligence [1, 2]. In the 2020 comparative table, developmental delay was absent in 8 of 8 TGDS patients assessed, and the severely affected infants in the series developed well once the respiratory problems had been resolved [3, 6]. Developmental delay and seizures are among the occasional findings of the clinical series preceding the gene, which may include cases of other aetiologies [2]. Hearing loss in an adult female patient, recurrent otitis with myringotomy in the 2015 infant and bronchial hyperreactivity in childhood have been described [3, 25]. Cryptorchidism, umbilical and inguinal hernias and a wide fontanelle complete the occasional findings [2, 3].

3.8. Prenatal phenotype

Smith lists nuchal oedema, heart disease, clubfoot and retrognathia with suspected Robin sequence as prenatal signs [2]. The 2017 fetus had severe heart disease, nuchal oedema, clubfoot, Robin sequence and anomalies of the index and middle fingers, and the pregnancy was terminated at 22 weeks [26]. The fetus of the 2025 cohort, examined at 24 weeks after termination, had mildly short long bones, fifth finger clinodactyly and micro/retrognathia [29]. In the two individuals reported in 2020, ultrasound showed a short femur, and in one of them also short limbs and retrognathia [4]. The absence of hyperphalangy in the second trimester may simply reflect gestational age [4].

3.9. KYNU-related form

The four patients with a Catel-Manzke-like phenotype and KYNU variants had index finger hyperphalangy, but a set of malformations closer to CNDD [6, 7]. The table compares them with the TGDS patients and with the patients of Shi and colleagues.

Source: Table 1 of Ehmke and colleagues [6]. ALCAPA, anomalous left coronary artery from the pulmonary artery; ASD, atrial septal defect; VSD, ventricular septal defect.

The first patient, of Caribbean origin, had a hypoplastic left heart operated on through to Fontan circulation, short stature from 2 years, radial deviation and clinodactyly of the index fingers with a bilateral supernumerary epiphyseal centre (clinical diagnosis of Catel-Manzke at 10 years), motor and language delay without cognitive deficit on formal assessment, attention deficit hyperactivity disorder, butterfly vertebrae at T10–T11 with scoliosis, congestive hepatomegaly and complete atrioventricular block at 13 years, treated with a pacemaker [6]. The second patient, the daughter of consanguineous Turkish parents, had tetralogy of Fallot and an undiagnosed anomalous origin of the left coronary artery that decompensated at surgery at 7 months, with extracorporeal membrane oxygenation for two weeks; there followed severe hypotonia, loss of skills, Lennox-Gastaut-type epilepsy, sensorineural hearing loss with cochlear and semicircular canal malformations and, at 3 years and 7 months, a height of −4.7 SD and head circumference of −6.4 SD; the authors acknowledge that part of the neurological picture results from hypoxia [6]. The third patient, also of consanguineous Turkish parents, had Manzke dysostosis with longitudinally bracketed epiphyses in the third proximal phalanges and second metacarpals, short middle fingers, laxity, atrial and ventricular septal defects, right renal agenesis, mild cognitive delay and a sister stillborn at term with similar findings [6].

The 2021 child had a hypoplastic left heart with mitral and aortic atresia operated on in stages (Norwood with Sano shunt, partial cavopulmonary connection at 5 months and total at 4 years), bilateral hypoplastic kidneys with stage 2 chronic kidney disease at 5 years (estimated glomerular filtration rate of 79 mL/min/1.73 m² by the Schwartz formula), short humeri, wedge-shaped lumbosacral vertebrae, clinodactyly of the fourth and fifth fingers, radial deviation and membranous polydactyly with duplication of proximal phalanges in the right hand, short fourth metatarsals and hallux valgus; at 5.5 years he measured 92 cm (13 cm below the 3rd centile) and had favourable psychomotor development [7]. In 2025, two infants with kynureninase deficiency without described hyperphalangy were reported (in the second, clinodactyly was excluded by radiography): a Dutch boy with increased nuchal fold at 11 weeks, Fallot-type double outlet right ventricle, short long bones, hemivertebrae, butterfly vertebrae, short ribs, bell-shaped chest, sensorineural deafness, tracheolaryngobronchomalacia and micrognathia, who died at 4 months of Candida sepsis after mediastinitis and necrotising enterocolitis; and an Afghan boy of consanguineous parents with a small left ventricle, bicuspid aortic valve, coarctation, atrial septal defect, butterfly vertebrae and hemivertebrae, hypothyroidism, left bronchomalacia and recurrent sepsis, with normal motor and cognitive development at 8 months [19]. The authors counted ten patients with kynureninase deficiency published before these two and draw attention to opportunistic infections and hypothyroidism as possible extensions of the phenotype [19]. Comparing TGDS patients with VCRL patients, the 2021 review concludes that the Robin sequence was present in all TGDS patients and in none of the VCRL patients, that bilateral hyperphalangy occurred in 9 of 12 TGDS patients and in 4 of 12 VCRL patients, and that mild developmental delay and cardiac and renal severity were greater in the VCRL forms [7].

3.10. Natural history and treated disease

The available descriptions are almost all of treated patients. The natural history without airway intervention is not documented in the series with molecular confirmation; the textbooks state that neonatal obstruction, associated with heart disease, can cause growth delay and that survival depends on getting through the neonatal period and early childhood [1, 2]. In the TGDS series, the only death recorded up to 2017 corresponded to a termination of pregnancy [6]. The adults described (19, 28 and 52 years) had orthopaedic complications, scoliosis or hearing loss, and the original patient had two healthy children [3]. At the re-examination of that patient at 27 and 47 years, the mandible had reached an almost normal profile, speech was hypernasal owing to a small residual defect of the hard palate, mobility of the index fingers was reduced but allowed pinch grip between thumb and index finger, there were progressive contractures of the fifth fingers, and the ossicle was completely fused with the proximal phalanx in the right hand and, in the operated left hand, with the phalanx and the metacarpal [11].

4. Clinical Recognition and Red Flags

4.1. Prenatal period

Prenatal suspicion almost always arises from micrognathia. The European Robin sequence guideline recommends considering the diagnosis when routine ultrasound shows an abnormal facial profile, referring to a reference centre for additional ultrasound or magnetic resonance imaging, and considering the Robin sequence from 18 weeks when the inferior facial angle is below 45.5° or mandibular length is 2 standard deviations below the mean; on magnetic resonance imaging, an isolated cleft palate, a tongue shape index above 80% and an inferior facial angle below 48° support the suspicion [20]. Very severe micrognathia may be visible from 12–14 weeks [31]. In Catel-Manzke syndrome, the combination of retrognathia with a short femur, nuchal oedema, heart disease or clubfoot is suggestive, but the digit anomalies may not be identifiable in the second trimester [2, 4, 26].

4.2. Newborn and infant

Any newborn with Robin sequence should have the index fingers examined and radiographed, because the hand sign is what separates Catel-Manzke syndrome from isolated Robin sequence [9]. The examination looks for a shortened index finger, with radial deviation at the base and ulnar curvature, bilaterally, and fifth finger clinodactyly; hand radiography shows the triangular ossicle at the base of the proximal phalanx [1, 3]. Examination of an infant with respiratory compromise should avoid changing the position of the head and neck [31]. An older child or adult with a deviated index finger and a history of cleft palate or neonatal micrognathia should be assessed in the same way, bearing in mind that the ossicle fuses with age and that in adulthood only a triangular proximal phalanx or a hypoplastic second metacarpal may remain [1, 3].

4.3. Warning and emergency signs

Airway obstruction is the main emergency. Stridor, desaturation, suprasternal and intercostal recession, deep pectus excavatum on each inspiration, feeding fatigue and early faltering weight gain indicate significant obstruction and require oximetry monitoring and assessment by a team experienced in the paediatric airway [20, 25, 31]. An infant with Robin sequence whose obstruction does not improve with positioning should be assessed for multilevel obstruction, including pharyngomalacia and laryngomalacia, which in the 2015 infant required supraglottoplasty and tracheostomy [20, 25]. The European guideline recommends stabilising infants presenting in severe respiratory distress according to paediatric resuscitation algorithms [20].

4.4. Clues to a KYNU-related form or to another diagnosis

In a child with index finger hyperphalangy, complex heart disease (hypoplastic left heart, tetralogy of Fallot), butterfly or wedge vertebrae, renal agenesis or hypoplasia, microcephaly, sensorineural hearing loss or developmental delay suggest a KYNU-related form or another CNDD, especially if there is no complete Robin sequence or if the parents are consanguineous [6–8]. Generalised laxity with dislocations, severe short stature with advanced carpal bone age, ossicles in several fingers, sensorineural hearing loss or ulnar (rather than radial) deviation of the index finger at the metacarpophalangeal joint suggest the differential diagnoses in section 6 [1, 40, 41].

4.5. Newborn screening

There is no newborn screening for Catel-Manzke syndrome or for CNDD; recognition depends on the clinical examination of the newborn with Robin sequence and on hand radiography [8, 9].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal published diagnostic criteria for Catel-Manzke syndrome. The clinical diagnosis rests on the combination of Robin sequence with Manzke dysostosis, and the definitive diagnosis requires biallelic pathogenic or likely pathogenic variants in TGDS [3, 4]. For the Robin sequence, the European guideline recommends using the three original criteria (micrognathia, glossoptosis and airway obstruction), with obstruction documented as obstructive sleep apnoea by polysomnography [20]. For CNDD there are no consensus criteria either: the diagnosis is established with suggestive findings and biallelic pathogenic or likely pathogenic variants in HAAO, KYNU or NADSYN1, and two variants of uncertain significance, or one pathogenic variant and one of uncertain significance in the same gene, neither establish nor exclude the diagnosis [8].

5.2. Radiology

Hand radiography is the test with the greatest diagnostic weight: it shows the accessory ossicle between the base of the proximal phalanx and the second metacarpal, hypoplasia of the proximal and middle phalanx and, sometimes, asymmetry of the proximal epiphysis of the middle finger [1, 9]. Its absence does not exclude the syndrome, because it has been described in carriers of biallelic variants and, in the second trimester, it may simply not be visible [4, 18, 29]. Spinal radiography may show anterior "beaking" of L2–L3, scoliosis or vertebral anomalies; segmentation anomalies, butterfly vertebrae and markedly shortened long bones point towards CNDD [2, 8, 25]. In the KYNU-related form, hand radiography may show, in addition to the ossicle, longitudinally bracketed epiphyses (delta phalanges) and segmentation of the second metacarpal [6]. In the Robin sequence, chest radiography or a skeletal survey is used to look for rib gaps when respiratory severity justifies it [31].

5.3. Genetic testing

The European guideline recommends prenatal genetic counselling when ultrasound shows retrognathia, referral of all newborns and infants with Robin sequence to a clinical geneticist at a reference centre as early as possible (or, if not feasible, at 6 months), and clinical and genetic reassessment at 2–3 years if the first assessment did not yield a diagnosis [20]. The minimum recommended work-up includes copy number variant (CNV) analysis and an exome-based panel of genes associated with the Robin sequence, ideally as a trio; when this is not feasible, at least CNV analysis and a limited Stickler syndrome panel [20]. This recommendation does not replace hand radiography: a panel limited to Stickler syndrome does not include TGDS, and a 2026 systematic review places TGDS among the genes most frequently involved in non-isolated Robin sequence (12 individuals, after SOX9, SNRPB and SATB2) [42]. The European guideline applies to patients with Robin sequence without a confirmed or strongly suspected syndromic diagnosis, so its genetic recommendation covers the patient with Catel-Manzke syndrome before the diagnosis is established, but not subsequent management, to which it applies by analogy [20].

When Manzke dysostosis is present, TGDS sequencing or a panel that includes it is the targeted test; when there is complex heart disease, vertebral or renal anomalies, or when TGDS is negative, exome sequencing with CNV analysis should include KYNU, HAAO and NADSYN1, and GeneReviews proposes a VACTERL multigene panel or exome/genome sequencing for CNDD [6–8]. The 2012 authors recommend including IMPAD1 in patients with Catel-Manzke syndrome and additional malformations (severe short stature, dislocations, numerous accessory bones, carpal synostosis) [27]. A typical patient without TGDS variants does not necessarily represent a failed test, because the phenotype is heterogeneous [9, 28].

5.4. Biochemistry when kynureninase deficiency is suspected

There is no biochemical test for the TGDS form [9]. In the KYNU-related form, urinary organic acid analysis by gas chromatography–mass spectrometry detected xanthurenic acid in the two patients tested in 2020 and in the 2021 child, and did not detect it in ten controls and patients with other inborn errors or in a heterozygous mother; in the 2021 family, the heterozygous mother had a mild increase [6, 7]. Plasma and urine metabolomics in two patients showed an increase in metabolites proximal to the block and a decrease in distal ones, and the authors proposed exploratory cut-offs in a specific clinical laboratory, derived from only two patients [6].

Source: Table 2 and results of Ehmke and colleagues (272 to 2087 controls per metabolite) [6]. GeneReviews describes the measurement of these metabolites and of NAD as investigational, without clinical validation and not a substitute for molecular confirmation [8, 37]. Blood NAD+ may be insensitive: in the adult kynureninase-deficient mouse, serum NAD+ was normal, and in one 2017 patient the fall in NAD+ (9-fold) was much smaller than the rise in 3-hydroxykynurenine (161-fold) [6]. Xanthurenic acid excretion does not necessarily correlate with the severity of the malformations, as shown by the siblings with hydroxykynureninuria without malformations [6]. In the two infants reported in 2025, xanthurenic acid and 3-hydroxykynurenine were increased in urinary organic acids and in the purine and pyrimidine profile, plasma metabolomics also showed 8-methoxykynurenate, which the authors consider a reliable marker, and whole-blood NAD+ and N-methyl-2-pyridone-5-carboxamide (2PY) were not decreased in the patient measured; in the four heterozygous parents, metabolites were normal [19].

5.5. Test limitations

Sequencing detects point variants and small insertions or deletions, but not single-exon deletions; in CNDD, sequencing detects more than 99% of known variants according to GeneReviews, but this proportion refers to the variants described and not to clinical sensitivity [8]. The homozygous 863 bp deletion of KYNU exon 5 was not seen on the comparative genomic hybridisation array, because no probe fell within the exon, nor in the first exome filter; only manual inspection of coverage revealed it, subsequently confirmed by long-range PCR (polymerase chain reaction) and Sanger sequencing [7]. The 85 kb deletion of KYNU exons 1 to 8 was detected by an exon-resolution array [6]. Panel content also limits diagnosis: in one 2025 infant, the prenatal exome analysed by phenotype terms and by a fetal anomaly panel that did not include KYNU was negative, and only postnatal reanalysis found the variant; the authors propose including KYNU in panels for multiple congenital anomalies, congenital heart disease and skeletal anomalies [19]. Apparent homozygosity requires testing both parents, because it may result from an undetected deletion on the other allele or from uniparental isodisomy, and the variant may have arisen de novo or in a mosaic parent [7, 8]. Interpretation of missense variants in TGDS now benefits from functional data, because the function of the enzyme is known, but no clinical assay is available [9, 29].

5.6. Report and variants of uncertain significance

The report should state the gene, the transcript with version (NM_014305.4 for TGDS; NM_003937.3 for KYNU), the Human Genome Variation Society (HGVS) c. and p. notation, zygosity, phase confirmed by parental testing and the ACMG/AMP (with the Association for Molecular Pathology) class of each variant [8, 10]. The c.298G>T variant is classified in ClinVar as pathogenic/likely pathogenic by several submitters and without conflicts [35]. A variant of uncertain significance in trans with c.298G>T in a patient with Manzke dysostosis should be reassessed with segregation, phenotype and structural and functional data; on its own, it does not confirm the diagnosis [8, 29].

5.7. Prenatal and preimplantation diagnosis

With both familial variants identified, carrier testing in relatives, prenatal diagnosis and preimplantation genetic diagnosis are possible [8]. The European guideline recommends offering genetic counselling when there is prenatal suspicion of Robin sequence and informing parents, at a reference centre, about postnatal respiratory and feeding difficulties and treatment options [20]. Prenatal trio exome sequencing identified the TGDS variants in the 24-week fetus of the 2025 cohort, from uncultured amniocytes [29].

5.8. Diagnostic algorithm

6. Differential Diagnosis

6.1. Comparative table

The differential diagnosis has two axes: the other causes of Robin sequence and the other causes of hyperphalangy or of an accessory ossicle of the index finger, most of which belong to the family of proteoglycan synthesis disorders [1, 6].

AD, autosomal dominant; AR, autosomal recessive.

6.2. KYNU-related forms and other CNDD

The overlap with CNDD is the most relevant in practice, because it changes prognosis and surveillance. The GeneReviews chapter on CNDD includes Catel-Manzke syndrome in its differential diagnosis: the hand malformation, with an accessory ossification centre, shortening and clinodactyly of the index finger, can occur in CNDD; the Robin sequence is more frequent in Catel-Manzke syndrome; and cardiac, vertebral and renal anomalies are much more frequent in CNDD [8]. The 2021 review found the Robin sequence in all TGDS patients and in none of the 12 VCRL patients, bilateral hyperphalangy in 9 of 12 TGDS patients and in 4 of 12 VCRL patients, and heart defects in all VCRL patients assessed, five of them with hypoplastic left heart [7]. The KYNU-related forms do not describe "classic" Catel-Manzke syndrome with Robin sequence: of the three patients reported in 2020, none had the complete sequence with cleft, although two had micro-retrognathia [6]. Urinary xanthurenic acid is the accessible discriminating test [6].

6.3. Proteoglycan synthesis dysplasias

Desbuquois dysplasia type 1 (CANT1) has a similar index finger anomaly, with an extra ossicle between the metacarpal and the proximal phalanx, but is distinguished by generalised laxity, by prominent lesser trochanters that give the proximal femur a "monkey wrench" appearance, by vertebral coronal clefts and by advanced carpal bone age; the Kim variant has short metacarpals, long phalanges and very advanced carpal ossification [1, 40]. XYLT1 deficiency shares the femoral changes and accelerated ossification, has lateral patellar dislocation and developmental delay, and Bone Dysplasias distinguishes it from Desbuquois dysplasia by the absence of the typical phalangeal changes [33]. Chondrodysplasia with joint dislocations, gPAPP type (IMPAD1) presents with Robin sequence, short-limbed short stature, hearing loss and multiple dislocations; two sisters with IMPAD1 variants had been diagnosed as "Catel-Manzke-like", and the authors recommend testing IMPAD1 in patients with Catel-Manzke syndrome and additional malformations [27, 41]. Temtamy syndrome (CHSY1) has a more severe hand phenotype, with hyperphalangy of the first three digits and shortening of the phalanges and metacarpals that Catel-Manzke syndrome does not have [3]; the overlap has been discussed since 2005 and was reinforced by the 2017 TGDS fetus with involvement of the middle fingers and halluces [26, 48, 51]. The Saudubray table of GAG synthesis defects summarises this group [32]. Desbuquois dysplasia, Baratela-Scott syndrome (XYLT1) and IMPAD1-related chondrodysplasia with joint dislocations belong to the group of dysplasias with congenital joint dislocations, and Temtamy syndrome to that of the brachydactylies.

6.4. Hyperphalangies due to transcription factors and isolated forms

Chitayat syndrome, caused by the recurrent variant NM_006494.4:c.266A>G p.(Tyr89Cys) in ERF, has index finger hyperphalangy with ulnar angulation at the metacarpophalangeal joint (the reverse of Catel-Manzke syndrome), hallux valgus and neonatal respiratory distress due to bronchomalacia, which may be confused with the obstruction of the Robin sequence; OMIM also describes prominent eyes, hypertelorism, a depressed nasal bridge, thick lips and an upturned nose, and the first patient (1993) required ventilation for more than a week owing to narrowing of the first- and second-generation bronchi with absent or immature cartilage [1, 46, 47]. In brachydactyly type C, due to GDF5 variants, there are extra ossification centres in the phalanges, mainly of the index and middle fingers, which fuse with maturation, short middle phalanges and shortening of the thumb metacarpal; expression is highly variable within the same family, and Bone Dysplasias notes that the Catel-Manzke ossicle may be confused with brachydactyly C, but is accompanied by other bone anomalies [50]. Ehmke and colleagues note that variants in ERF and GDF5, genes outside the proteoglycan pathway, also cause hyperphalangy [6]. Chitayat syndrome and brachydactyly type C belong to the group of brachydactylies.

6.5. Devriendt syndrome and undiagnosed cases

In Devriendt syndrome, the index finger ossicle lies at the distal end of the abnormal metacarpal and the first metacarpal is also malformed, with severe short stature and intellectual disability [1]. One KYNU patient reported in 2020 had segmentation of the second metacarpal, short stature, micrognathia, a high palate, delay and radial deviation of the index finger, and the authors suggested the tryptophan pathway genes as candidates for Devriendt syndrome, a hypothesis that has not been tested [6]. In 2015, a Catel-Manzke-like patient (bilateral hyperphalangy of the second finger, unilateral delta phalanx of the thumb, growth deficiency, heart disease and vertebral anomalies) had no variants in the known genes after exome sequencing, at a time when KYNU had not yet been associated with the phenotype [28].

6.6. Other causes of Robin sequence

Isolated Robin sequence and Stickler syndrome, 22q11.2 deletion, Treacher Collins, Nager, cerebro-costo-mandibular syndrome, SATB2-associated syndrome and TARP syndrome, among others, have normal hands or different anomalies (for example, rib gaps in cerebro-costo-mandibular syndrome) [31, 42]. Normal hand radiography does not exclude TGDS, but the combination of normal hands with other syndromic signs points towards those entities [4, 18].

7. Treatment and Risk Management Strategies

7.1. Principles

There is no cause-directed treatment for either Catel-Manzke syndrome or the KYNU-related forms, and no medicine has authorisation from the United States Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for these indications [8, 9]. Management is directed at the manifestations and, in the infant, centres on the Robin sequence: respiratory support for airway obstruction, surgical correction of the cleft palate and heart disease, and orthopaedic follow-up are the interventions described in the reference textbooks [1, 2]. There is no specific guideline for Catel-Manzke syndrome. The European Robin sequence guideline, published in 2024 by the European Reference Network ERN CRANIO, excludes confirmed syndromic Robin sequence from its scope; its recommendations apply here by analogy, because the pathophysiology of the obstruction, feeding and cleft is the same, and this extrapolation is stated at each point [20]. Management of the KYNU-related form follows the GeneReviews chapter on CNDD, which also does not rely on published clinical guidelines [8].

7.2. Delivery and neonatal stabilisation

When the Robin sequence is suspected prenatally, the European guideline recommends planning delivery with a physician experienced in the difficult neonatal airway present and preparing a risk team that includes otorhinolaryngology, paediatric anaesthesia and neonatology, ideally in a unit experienced in Robin sequence or in liaison with one [20]. The newborn in severe respiratory distress is stabilised according to paediatric and neonatal resuscitation algorithms; endotracheal intubation is a life-support measure and a bridge to the definitive decision when non-surgical measures fail [20]. In the TGDS series, one newborn required intubation and ventilation immediately after birth [3].

7.3. Airway obstruction

The European guideline recommends screening for respiratory problems with regular clinical assessment and continuous oximetry, performing baseline polysomnography in all newborns with suspected Robin sequence, repeating it to assess the outcome of treatment or a deterioration, and performing flexible nasendoscopy in all of them to identify all levels of obstruction, with the treatment decision taken by the multidisciplinary team [20]. Non-surgical treatment comes first: prone or lateral positioning with continuous oximetry, also at home, as first line (85% consensus), nasopharyngeal airway, palatal plate and continuous positive airway pressure; the panel agreed (100%) that the benefit of prone positioning must be weighed against the risk of sudden infant death, and (75%) that no non-surgical intervention has shown superiority, so the choice depends on effectiveness and local experience [20]. If obstructive apnoea is not controlled, the guideline recommends escalating support and, when non-surgical intervention is still needed at 6–9 months, reassessing with the parents whether to continue or switch to surgery [20].

In cases that do not respond, the guideline recommends mandibular distraction osteogenesis or tracheostomy, after excluding obstruction below the base of the tongue; glossopexy is an alternative in experienced centres, but respiratory and feeding outcomes are better with distraction; and it recommends considering tracheostomy rather than distraction in patients who are syndromic, of low birth weight or with neurological impairment [20]. For distraction, it recommends overcorrection, because of the intrinsic disturbance of mandibular growth in the Robin sequence, and three-dimensional planning when an internal device is used [20]. In Catel-Manzke syndrome, tracheostomy (two infants, one of them with nocturnal ventilation), supraglottoplasty for pharyngo/laryngomalacia and mandibular distraction have been described [3, 25]. The guideline does not distinguish Catel-Manzke syndrome from the other syndromic forms, and the sources consulted do not compare outcomes of distraction and tracheostomy in this syndrome.

7.4. Feeding and growth

The European guideline recommends standardised feeding assessment protocols from the first visit, standardised growth charts, dietetic consultation and assessment by a speech and language therapist in all infants with Robin sequence, and recording of intake and growth (weight, length and head circumference) to evaluate interventions, with closer monitoring around surgery [20]. Treatment starts with high-calorie formulas, moves to a nasogastric tube when modified oral intake is insufficient and to gastrostomy when airway obstruction does not respond to interventions; the guideline stresses that respiratory intervention is part of the nutritional strategy and that glossopexy and distraction carry their own postoperative feeding risks [20]. Study of swallowing and oesophageal function (electromyography, fibreoptic endoscopic evaluation, oesophageal monitoring) may guide the team in severe cases [20]. The 2015 infant illustrates this sequence: pharyngeal dysphagia and severe faltering weight did not respond to calorie densification, a gastrostomy was placed at 2.5 months and weight only recovered after tracheostomy [25].

7.5. Cleft palate, speech, hearing and teeth

Palatoplasty has been described in the TGDS series (for example, at 13 months in one female patient) and is one of the main interventions indicated by Bone Dysplasias [1, 4]. The European guideline, with 70.5% consensus, considers it appropriate to perform polysomnography before palatoplasty, to predict whether surgery will induce or worsen obstruction, and to use its results to decide the type and timing of surgery; with 82% consensus, it considers it appropriate to repeat polysomnography at least 3 months after palatal or speech-correcting surgery; and it recommends avoiding pharyngoplasty, which may induce obstructive apnoea or cause it to recur [20]. Speech requires early stimulation before and after palatoplasty, formal assessment by a cleft-specialist speech and language therapist at 2 and 3 years and screening from 5 years until the end of growth, at least every 5 years [20]. The guideline recommends a dental visit at 5–6 years with orthopantomography to screen for hypodontia and six-monthly review until skeletal maturity, and informing parents that functional and aesthetic problems may arise at maturity, treatable with mandibular and maxillary advancement surgery [20]. Recurrent otitis may require myringotomy with grommets [25].

7.6. Heart disease

Heart defects in the TGDS form are usually septal defects, sometimes with spontaneous closure, and are treated according to the usual indications; surgical correction is one of the main interventions mentioned by Bone Dysplasias [1, 3, 25]. In the KYNU-related form, heart defects are complex and require staged surgery (Norwood, cavopulmonary connection, Fontan) and rhythm follow-up: one patient had complete atrioventricular block at 13 years and one female patient required a pacemaker after surgery [6, 7]. An undiagnosed anomalous origin of the left coronary artery caused ventricular decompensation during surgery in a KYNU patient, and GeneReviews includes this anomaly among the heart defects of CNDD [6, 8].

7.7. Orthopaedics and hands

Orthopaedic follow-up addresses Perthes disease, genu valgum, hip dysplasia, joint hypermobility, scoliosis and chest deformities [2–4]. In the TGDS series, bilateral osteotomy for genu valgum at ~20 years, bilateral femoral osteotomy for hip dysplasia at 9 years and bilateral Perthes disease with incomplete recovery have been described [3, 4]. The index finger deformity is orthopaedic and not life-threatening; one female patient received exercise therapy for the phalangeal deformities, and the sources consulted do not describe outcomes of surgical correction of the index finger in this syndrome [4, 9].

7.8. KYNU-related form and other CNDD

After a diagnosis of CNDD, GeneReviews recommends measuring weight, length and head circumference, looking for cleft palate, audiological assessment, radiographs of the whole spine (with computed tomography if a cervical anomaly is suspected), spinal ultrasound or magnetic resonance imaging in the presence of sacral stigmata, echocardiography, renal and bladder ultrasound, abdominal ultrasound (polysplenia, hepatomegaly), developmental and neurological assessment (brain magnetic resonance imaging in the presence of seizures, microcephaly or neuromuscular findings), thyroid-stimulating hormone (TSH) and free thyroxine, total calcium with parathyroid hormone (PTH) if low, and baseline ophthalmological assessment [8]. It also recommends standard treatment of heart defects, cleft palate, limb anomalies, scoliosis, tethered cord, renal anomalies, tracheo-oesophageal fistula, pyloric stenosis, laryngeal web, polysplenia, strabismus and ptosis, as well as hearing loss, developmental delay, epilepsy, hypothyroidism and hypoparathyroidism [8]. It includes occupational therapy, feeding therapy (thickened or chilled foods, nasogastric tube or gastrostomy in severe cases) and assessment for augmentative and alternative communication [8]. In patients with a single kidney or reduced renal function, it recommends avoiding nephrotoxic drugs [8]. Epilepsy is treated with standard antiseizure medications, none of which has shown specific efficacy in this disease [8]. In the KYNU patient with Lennox-Gastaut-type epilepsy, valproate and levetiracetam improved the electroencephalographic abnormalities and the seizures, in a case report that does not establish a specific treatment [6].

NAD+ precursors and pyridoxine are not an established treatment, and the evidence is scarce. In Haao- or Kynu-null mice, prevention of NAD deficiency during gestation, with maternal niacin supplementation (a term covering nicotinic acid, nicotinamide, nicotinamide riboside and nicotinamide mononucleotide), prevented the malformations [19, 21]. The 2023 GeneReviews chapter does not recommend niacin, and supplementation started after birth cannot reverse malformations that have already formed [8, 37]. In 2025, Goorden and colleagues described the first treatment of patients with kynureninase deficiency: two infants received oral nicotinamide from 2–3 weeks of life and pyridoxine (vitamin B6, the kynureninase cofactor) added weeks later, intravenously when the oral route was not possible [19]. The doses were based on the Dutch paediatric formulary and not on dose–response studies [19].

Source: Goorden and colleagues, 2025 [19]. This is a two-case series, without a comparison group and with short follow-up, and the use is off-label. The same authors cite four patients with NADSYN1 deficiency treated for 6–10 weeks with nicotinamide at 100 to 400 mg/day, with a small effect on NAD+ and no reported adverse effects [19]. They prefer nicotinamide to nicotinic acid because of the flushing caused by the latter, note that high, prolonged doses of nicotinamide may inhibit NAD+-consuming enzymes by feedback, that nicotinamide riboside and mononucleotide have limited bioavailability and are not available in pharmaceutical grade in all countries, and propose, for treated patients, motor, cognitive, growth and skeletal assessment at baseline and then annually, monitoring of kynurenine metabolites in blood and urine and screening for toxicity of prolonged supplementation [19]. They also consider that patients with CNDD are at risk of pellagra (diarrhoea, dermatitis and dementia) when niacin intake is limited, as in acute illness and fasting, and that in these situations intravenous administration of vitamins B3 and B6 is indicated; they describe severe episodes of pellagra-like dermatitis in two patients with NADSYN1 deficiency [19]. Ehmke and colleagues had considered it uncertain, in 2020, whether supplementation would improve development or whether there was a risk of pellagra, noting that 1 mg of niacin is equivalent to 60 mg of tryptophan and that, after birth, about half of niacin equivalents derive from tryptophan [6].

There is no guideline setting doses, so the doses of the 2025 series are the only published reference for this indication. Comparison with national labels is made with reservations. In Infomed, a search for the name "nicotinamida" returned no medicine authorised in Portugal on the date of consultation. For pyridoxine, the summary of product characteristics (SmPC) of Piridoxina Labesfal® (40 mg tablets; there is also a 150 mg/ml solution for injection) indicates, in pyridoxine deficiency, 5 to 25 mg/day orally for 3 weeks, up to 150 mg/day not exceeding 3 weeks, and, in hereditary disorders of amino acid metabolism, 100 to 500 mg/day; the doses of the 2025 series (25–50 mg/day in an infant) are outside the approved indications [19, 52]. The same SmPC contraindicates intravenous pyridoxine in patients with heart disease and associates prolonged administration of high doses with severe peripheral neuropathy, two warnings relevant in a disease in which almost all patients have heart disease and in which the 2025 infants received intravenous pyridoxine during surgery [8, 19, 52]. The decision to treat should be made case by case, in a centre experienced in inherited metabolic diseases, with informed consent for off-label use.

7.9. Regulatory status and trials

Source: ClinicalTrials.gov, application programming interface v2, consulted on 31 October 2026; GeneReviews chapter on CNDD [8].

7.10. Recent developments (2025–2026)

The publication by Goorden and colleagues (online on 19 July 2025) falls shortly before the 12-month window ending in October 2026, but it is the only published human therapeutic experience [19]. The sources consulted record no press releases, regulatory applications or clinical trials for Catel-Manzke syndrome or CNDD in the period. The authors of the 2025 work consider that knowing the function of TGDS will help with variant interpretation and genetic counselling; the idea of reactivating enzymes with metabolites is, for now, a hypothesis without clinical application [29].

7.11. Anaesthesia, perioperative care, pregnancy and transition

The difficult airway accompanies patients with Robin sequence at every anaesthetic, especially before palatoplasty, mandibular distraction and cardiac surgery; the European guideline includes paediatric anaesthesia in the team from delivery, and polysomnography before and after palatal surgery documents the respiratory risk [20]. In the KYNU-related form with a single kidney or renal impairment, nephrotoxic drugs should also be avoided perioperatively [8]. The sources consulted do not describe pregnancies in women with Catel-Manzke syndrome; the original patient had two healthy children [3]. Transition to adult care should maintain orthopaedic and, when indicated, maxillofacial follow-up, because the European guideline anticipates mandibular and maxillary advancement surgery at skeletal maturity [2, 20].

7.12. Summary of applicable recommendations

The sources consulted record no recommendations from specific societies for Catel-Manzke syndrome and no published divergences on these approaches; the European guideline does not formally cover syndromic Robin sequence, and its authors acknowledge that the evidence on the airway is mainly observational, with studies that do not always separate isolated from syndromic Robin sequence [20]. There are also consensus statements from other societies on the Robin sequence.

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risk

TGDS-associated Catel-Manzke syndrome and the KYNU-related forms are autosomal recessive [1, 2, 8]. When both parents are heterozygous, each pregnancy has a 25% probability of an affected child, 50% of an asymptomatic carrier and 25% of a child without the variant [8]. The parents should be tested to confirm that both are carriers, because this defines the risk [8]. If only one parent has the variant, with paternity and maternity confirmed, the possibilities are a de novo variant in the proband or in a mosaic parent; if the proband appears homozygous, a deletion on the other allele not detected by sequencing or uniparental isodisomy must be considered [8]. Isodisomy is not theoretical in this family of diseases: the 2021 child was homozygous for the KYNU exon 5 deletion because he inherited two copies of maternal chromosome 2, and the mother was the only carrier; in this scenario, the recurrence risk is much lower than 25% [7]. Heterozygotes have no manifestations [8].

8.2. Obstetric history

Several families had previous pregnancy losses: three first-trimester miscarriages in the mother of the 2015 infant, two early miscarriages in the parents of one of the individuals reported in 2020 and, in a KYNU family, two miscarriages and a term stillbirth with findings similar to those of the proband [4, 6, 25]. None of these losses was studied genetically, and the sources do not allow them to be attributed to the disease [4, 25]. In the mouse, complete inactivation of Tgds is lethal early in embryogenesis [29].

8.3. Testing of relatives, carriers and consanguinity

Once the variants have been identified, carrier testing can be offered to relatives, and the GeneReviews chapter on CNDD recommends clarifying the genetic status of apparently asymptomatic older and younger siblings in order to look for occult malformations (cardiac, renal, vertebral) [8]. Carrier testing of the partner of a known carrier is appropriate, especially when there is consanguinity, which was present in the two Turkish families with KYNU-related forms and absent in the 11 TGDS families of the 2020 series [4, 6, 8]. In Europe, the allele frequency of c.298G>T is about 0.1% in non-Finnish Europeans in gnomAD, which allows estimation of the risk that an affected adult or carrier has a partner carrying this variant, but not the totality of TGDS variants [3, 36].

8.4. Prenatal and preimplantation diagnosis

With the familial variants known, prenatal diagnosis and preimplantation genetic diagnosis are possible [8]. Ultrasound may show retrognathia, short femur, nuchal oedema, heart disease or clubfoot, but a normal scan does not exclude the disease, and hyperphalangy may not be visible in the second trimester [2, 4, 26]. Genetic counselling and discussion of reproductive options should ideally take place before pregnancy, and GeneReviews recommends offering them to young adults who are affected, carriers or at risk of being carriers [8]. For families with CNDD, maternal supplementation with NAD+ precursors in a subsequent pregnancy has no demonstrated efficacy in humans and was considered speculative in 2021 [7, 21]. In the Dutch family reported in 2025, the team considered and declined high-dose maternal supplementation during the pregnancy of the affected infant because of the risk of maternal toxicity, and the infant was born with malformations although the mother had taken from the outset a multivitamin containing 33 mg of nicotinamide per day; in the next pregnancy, the mother took on her own initiative nicotinamide riboside (300 mg three times a day from 3 weeks, reduced to 200 mg twice a day at 10 weeks) with the same multivitamin, without adverse effects and with normal liver enzymes; the daughter did not have the disease, so the case informs only about tolerability [19].

8.5. Minors

In the KYNU-related form and in the other CNDD, GeneReviews recommends clarifying early the genetic status of apparently healthy minor siblings, because the diagnosis leads to a search for occult malformations with clinical benefit [8]. Carrier testing for reproductive purposes falls within the counselling that GeneReviews recommends offering to young adults who are affected, carriers or at risk of being carriers [8]. Heterozygous carriers of TGDS variants are healthy [3, 25].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence

Orphanet classifies the syndrome with a worldwide point prevalence below 1 per 1,000,000 and records 33 cases, a number that refers to the clinical syndrome and includes cases preceding the gene; the subgroup with TGDS confirmation is smaller [5, 9]. Smith estimates 1 per 1,000,000 births and more than 30 patients described, and Miller and colleagues counted about 40 in 2020 [2, 18]. Data with molecular confirmation amount to 11 individuals in 2020 (including one fetus), isolated later cases and a cohort of five individuals in 2025, partly overlapping [4, 18, 29]. In a systematic review of 107 genetic studies of the Robin sequence, TGDS was found in 12 individuals with non-isolated Robin sequence [42]. These counts measure published cases and not population frequency.

9.2. Populations and founder effect

The c.298G>T variant is the most frequent and, given the shared haplotype, probably has a European founder origin; patients with the variant had German, French, Dutch, Czech and British/South American ancestry, and the 2017 fetus was of Russian origin [3, 4, 25]. In gnomAD v4.1, the allele frequency is 0.100% in non-Finnish Europeans and much lower in other populations (0.017% in Africans and African Americans in exomes, 0.003% in Latin Americans, absent in East Asians) [36]. Ehmke and colleagues estimated, from a carrier rate of 0.002 in Europe, about one homozygote per million, which makes the frequency of the syndrome ancestry-dependent [3, 9]. There are patients of other origins with different variants: a patient of Cameroonian origin with two private variants and the Dutch patients with c.700T>C [3, 4]. KYNU-related forms with hyperphalangy have been described in a patient of Caribbean origin, in two consanguineous Turkish families and in a child of non-consanguineous parents with maternal isodisomy; the patients with kynureninase deficiency reported in 2025 were a Dutch infant and an Afghan infant of consanguineous parents, the first diagnosed in the Netherlands [6, 7, 19]. In one of these infants, the maternal variant c.256dup had 250 heterozygotes among 1,179,312 non-Finnish Europeans in gnomAD v4.1 [19]. CNDD, for the three genes, totalled 27 individuals from 25 families in 2023 [8].

9.3. Geographical gaps

The sources consulted include no cases from Portugal or Brazil, nor frequency data for the founder variant in these populations; the 2014 cohort includes a patient of British and South American ancestry without a specified country [3]. Representatives of Portuguese centres took part in drafting the European Robin sequence guideline [20]. The absence of data in the sources consulted does not demonstrate the absence of patients.

9.4. European networks and patient organisations

ERN CRANIO (https://www.ern-cranio.eu/), dedicated to craniofacial anomalies and rare ENT disorders, published the European Robin sequence guideline and recommends centralisation of care in reference centres [20]. ERN BOND (https://ernbond.eu/) covers rare bone diseases and ERN ITHACA (https://ern-ithaca.eu/) malformation syndromes and intellectual disability. The organisations cited by the Oxford Desk Reference include the Cleft Lip and Palate Association (CLAPA, United Kingdom), the American Cleft Palate–Craniofacial Association (ACPA), Contact a Family and the Pierre Robin Network [31]. The European guideline recommends informing parents early about patient organisations and providing peer contact [20].

10. Illustrative Clinical Case

10.1. Infant with Robin sequence without cleft and with hyperphalangy (Pferdehirt and colleagues, 2015)

A boy was born at 38 weeks and 4 days, by uncomplicated vaginal delivery, to a 29-year-old mother with three first-trimester miscarriages of unknown cause and one healthy child by the same father; the father was of German and the mother of Czech ancestry, without known consanguinity, and prenatal ultrasound scans had been normal [25]. Faltering growth began at 3 weeks and, at 2 months, the weight z-score was −8.22 (World Health Organization charts), despite increased calorie density and feeding therapy [25]. A modified barium swallow study showed pharyngeal dysphagia and fatigue with feeds, and a gastrostomy was placed at 2.5 months; gastro-oesophageal reflux was also diagnosed [25]. During an admission for faltering weight, stridor and desaturations down to 85% were noted; otorhinolaryngology diagnosed severe pharyngomalacia and laryngomalacia and performed a supraglottoplasty [25]. At 6 months he had mixed sleep apnoea and respiratory failure due to airway hypotonia and oropharyngeal weakness, and at 7 months he underwent tracheostomy with nocturnal ventilation; he also had myringotomy with grommets for recurrent otitis [25].

At 12 months he weighed 8.42 kg (z −1.22), measured 72.4 cm (z −1.36) and had a head circumference of 45.9 cm (z −0.13); he received most of his calories by gastrostomy and tolerated small amounts orally [25]. Examination showed prominent overriding sutures, a tubular-appearing nose with a high nasal bridge and narrow nostrils, retrognathia, a high narrow palate with a small groove of the posterior soft palate, ankyloglossia, mild palpebral oedema with proptosis, long fingers, deviated and overlapping index fingers and mild pectus [25]. Radiography of the right hand showed a mildly hypoplastic proximal phalanx of the second finger with an additional bone at its base and radial deviation of the index finger; lateral spinal radiography showed anterior "beaking" of L2 and L3; echocardiography at 3 months showed a small patent foramen ovale and ductus arteriosus, resolved by 6 months; neurological examination and brain magnetic resonance imaging were normal, and karyotype, array, very-long-chain fatty acids and lysosomal panel were normal [25]. Sanger sequencing of TGDS showed homozygosity for c.298G>T p.(Ala100Ser) (NM_014305.4), with both parents heterozygous [10, 25]. Figure 1 of the article brings together the facial photograph, the hand radiograph and the family electropherogram: https://pmc.ncbi.nlm.nih.gov/articles/PMC4563870/figure/f0005/ [25].

The authors attributed the faltering weight to the complications of the Robin sequence, because weight improved with gastrostomy and tracheostomy, and placed the patient at the severe end of the TGDS spectrum [25]. The case shows that the absence of a cleft does not exclude the syndrome, that obstruction may occur at several levels (base of tongue, pharynx and larynx) and that the same homozygous variant as in Catel and Manzke's original patient, with a favourable course at 52 years, can accompany a severe neonatal picture [3, 25]. The sequence of interventions corresponds to the escalation anticipated by the European guideline (nutritional support, assessment of all levels of obstruction and tracheostomy in a syndromic patient with obstruction below the base of the tongue), published after the case [20].

10.2. Comparison case: KYNU-related form with hyperphalangy and heart disease (Ehmke and colleagues, 2020)

A boy of Caribbean origin, born at 36 weeks weighing 2900 g (−2.16 SD), had a hypoplastic left heart diagnosed shortly after birth and operated on through to Fontan circulation; short stature became evident at 2 years, and the radial deviation with clinodactyly of the index fingers led to radiographs that showed a bilateral supernumerary epiphyseal centre at the base of the proximal phalanx of the index finger and to a clinical diagnosis of Catel-Manzke syndrome at 10 years [6]. He had motor and language delay without cognitive deficit on formal assessment, attention deficit hyperactivity disorder, micro-retrognathia with a high palate, butterfly vertebrae at T10–T11 with scoliosis and, at 13 years and 3 months, complete atrioventricular block treated with a pacemaker [6]. The array showed an 85 kb maternal deletion (KYNU exons 1–8), the exome a non-maternal variant NM_003937.3:c.1282C>T p.(Arg428Trp), and metabolomics and urinary organic acids showed increased 3-hydroxykynurenine and xanthurenic acid [6, 10]. Figure 1 of the article shows the hands, face and spine of this and the other two patients: https://pmc.ncbi.nlm.nih.gov/articles/PMC10521254/figure/F1/ [6]. Complex heart disease and vertebral anomalies, without a complete Robin sequence, are the features that distinguish this form from the TGDS-associated syndrome [6, 7].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

The prognosis of TGDS-associated Catel-Manzke syndrome depends mainly on the severity of airway obstruction in the first year and, in a minority, on heart disease [1, 2]. Once that period is over, the patients described develop normally: developmental delay was absent in the 8 TGDS patients assessed in the 2020 comparison, the great majority of survivors have normal intelligence, and growth may normalise when the initial delay was secondary to the airway [1, 2, 6, 25]. Some patients retain short stature, sometimes disproportionate and marked (−4.4 SD in an adolescent girl) [4]. Adulthood is documented up to 52 years, with orthopaedic complications (Perthes disease, genu valgum, hip dysplasia), scoliosis, brachymetacarpia and hearing loss, and with offspring [3, 4]. With age, the index finger ossicle fuses with the proximal phalanx [2, 3]. The sources consulted provide no survival or mortality data beyond one termination of pregnancy in the molecular series [6].

In the KYNU-related form, the prognosis is that of CNDD and depends on the malformations: heart defects are complex and require staged surgery, renal function may be reduced from childhood, and developmental delay is more frequent [6–8]. Of the two infants described in 2025, one died at 4 months of sepsis and the other had normal development at 8 months [19]. In CNDD as a whole, of the nine known non-survivors in 2023, five were terminations or pregnancy losses and four died in the first year from severe malformations, and the oldest living patient was 30 years old [8].

11.2. Surveillance table

The table combines the recommendations of the European Robin sequence guideline, applied by analogy, with those of the GeneReviews chapter on CNDD for the KYNU-related form and with the orthopaedic follow-up indicated in the reference textbooks. The sources consulted do not define syndrome-specific numerical action thresholds; the thresholds shown are those of the sources.

12. Summary and Final Considerations

Catel-Manzke syndrome is a rare autosomal recessive disease, described by Catel in 1961 and characterised radiologically by Manzke in 1966, that combines the Robin sequence with bilateral index finger hyperphalangy: an accessory ossicle between the second metacarpal and the proximal phalanx causes radial deviation at the base and ulnar clinodactyly of the finger [2, 3]. Since 2014 it has been known that the main cause is biallelic variants in TGDS, with a European founder variant, c.298G>T p.(Ala100Ser), present in about two thirds of the alleles of the first patients and with an allele frequency of 0.1% in non-Finnish Europeans [3, 25, 36]. In 2025 it was established that TGDS produces a metabolite that reactivates UXS1 when the latter becomes trapped with NADH, and that its absence impairs the synthesis of UDP-xylose and of glycans required for the skeleton, which places the syndrome in the group of proteoglycan synthesis disorders, alongside the Desbuquois dysplasias, gPAPP deficiency and Temtamy syndrome [29, 32].

The phenotype is broader than the classic definition. The Robin sequence is almost constant, but cleft palate and hyperphalangy may be absent; short stature, sometimes disproportionate, is common; heart disease affects a minority and is usually simple; and intelligence is usually normal [4, 6, 18]. The clinical phenotype is heterogeneous: biallelic variants in KYNU, a gene of the NAD synthesis pathway, cause a form with hyperphalangy, complex heart disease, vertebral and renal anomalies and developmental delay, which belongs to congenital NAD deficiency disorder and is recognised by urinary xanthurenic acid; IMPAD1 variants and cases without an identified cause complete the Catel-Manzke-like group [6–8, 27].

In practice, every newborn with Robin sequence should have the index fingers examined and radiographed, be referred early to clinical genetics and undergo CNV analysis and a Robin gene panel that includes TGDS; a form with cardiac, vertebral or renal malformations should broaden testing to KYNU, HAAO and NADSYN1 [8, 9, 20]. There is no targeted treatment and there are no clinical trials; management follows, by analogy, the European Robin sequence guideline for the airway, feeding, cleft, speech and teeth, and adds orthopaedic follow-up and, in the KYNU-related form, the renal, hearing, ophthalmological and endocrine surveillance of GeneReviews [2, 8, 20]. In the KYNU-related form, prevention with niacin has data only in mice, and postnatal treatment with nicotinamide and pyridoxine has been described in two infants, off-label and with short follow-up [8, 19, 21]. Genetic counselling follows recessive inheritance, with attention to uniparental isodisomies and to the frequency of the founder variant in European populations [7, 36].

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