STAR Syndrome (CCNQ/FAM58A)

X-linked dominant malformation syndrome, described only in females, defined by the association of toe syndactyly, telecanthus, anogenital malformations and renal malformations, caused by loss of function of the CCNQ gene (formerly FAM58A), which encodes cyclin M, the activating subunit of the kinase CDK10.

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Founding description

In 1996, Green, Sandford and Davison described in the Journal of Medical Genetics a mother and daughter with a combination of anal, renal, genital and foot anomalies that did not correspond to any known syndrome [29]. The mother had been born with anal stenosis and rectovaginal fistula, marked clitoromegaly, a right pelvic kidney, left hydronephrosis, a narrow nose, an asymptomatic ventricular septal defect and syndactyly of toes 3 to 5 of the left foot and 4 and 5 of the right foot; the daughter had anal stenosis without fistula, clitoromegaly, a solitary pelvic kidney and syndactyly of toes 3 to 5 on the left and 2 to 5 on the right [3]. Both had short stature and unusual facies [29]. The authors interpreted the transmission as autosomal dominant and drew attention to the need to distinguish the condition from Townes-Brocks syndrome; the later OMIM review considers the same pedigree compatible with X-linked inheritance [3, 29].

1.2. Definition of the syndrome and identification of the gene

Twelve years later, Unger and colleagues brought together four unrelated girls with the same constellation of facial dysmorphism and malformations and found that it matched the Green family [15]. Toe syndactyly, telecanthus and anogenital and renal malformations were present in all, and the initials of these four elements gave the name STAR syndrome [15]. The cardinal signs were defined as a characteristic facies, with apparent telecanthus and a broad, trifid nasal tip, variable syndactyly of toes 2 to 5, hypoplastic labia, anal atresia and urogenital malformations, with normal intellect [3]. Because of the clinical overlap with Townes-Brocks, Okihiro and Feingold syndromes, the genes SALL1, SALL4 and MYCN were studied first, without pathogenic variants [3]. Array comparative genomic hybridisation (array CGH) in the most severely affected patient revealed a heterozygous deletion at Xq28 removing exons 1 and 2 of a gene of then unknown function, FAM58A; a second patient had another de novo deletion of the same gene, and the remaining two patients and Green's mother-daughter pair had point variants [3, 7].

1.3. From orphan protein to cyclin M

In 2013, Guen and colleagues showed that the product of FAM58A is the activating cyclin of CDK10, a cyclin-dependent kinase (CDK) that until then had no known regulatory subunit, and named it cyclin M [30]. The mutant forms of cyclin M associated with the syndrome did not bind CDK10, and the CDK10/cyclin M complex phosphorylated the transcription factor ETS2 and promoted its proteasomal degradation; a patient's cells had increased ETS2 levels [30]. In 2016, the same group showed that deficiency of the complex lengthens primary cilia and found elongated cilia in a patient's kidney biopsy, which led them to propose STAR syndrome as a ciliopathy [31].

1.4. Current nomenclature and definition of the entity

The approved gene symbol is now CCNQ (cyclin Q); FAM58A and CycM are earlier designations that persist in the clinical literature up to 2017 [2, 7]. The names cyclin M and cyclin Q refer to the same protein: the first was used by the group that identified its function, the second corresponds to the official symbol [30, 32]. STAR syndrome is defined as the malformation picture of toe syndactyly, telecanthus and anogenital and renal malformations caused by a heterozygous loss-of-function variant of CCNQ or by a deletion that includes it, in a female patient [1, 3]. OMIM records a single phenotype for the gene (#300707) [7].

2. Molecular Genetics and Pathophysiology

2.1. The CCNQ gene and cyclin M

CCNQ lies at Xq28, on the minus strand, at GRCh38 coordinates X:153,587,925–153,599,139, about 0.56 Mb centromeric to MECP2 [7]. The MANE Select (Matched Annotation from NCBI and EMBL-EBI) transcript NM_152274.5 has five exons and encodes a protein of 248 amino acids [8]. In the 2008 description, the coding region measured 642 base pairs and the protein 214 amino acids, a shorter annotation that explains the difference in numbering of the historical variants [7, 33]. The protein contains a "cyclin box" fold domain, characteristic of the cyclins that regulate the cell cycle and transcription [7]. In expressed sequences, the gene was detected in 27 of 48 adult tissues, including kidney, colon, cervix and uterus, but not in the heart [7]. Homologues exist on the X chromosome of the chimpanzee and the dog, but no true homologues were found in the mouse or the rat, which limits murine models [7].

2.2. The CDK10/cyclin M complex and its substrates

Cyclin M binds CDK10 and forms a heterodimer with kinase activity [30]. The substrates described include the transcription factor ETS2, whose proteasomal degradation the complex promotes, the kinase PKN2, phosphorylated at threonines 121 and 124 of the RhoA-binding domain, and, in vitro, the carboxy-terminal domain of RNA polymerase II, c-MYC and RB1 [30–32]. A screen in HEK cells with an analogue-sensitive kinase identified 89 phosphorylation sites in 66 proteins linked to the cell cycle, translation, the stress response and transcription, which places CDK10 in an intermediate position between the cell-cycle and the transcriptional CDKs [32]. Unger and colleagues also showed, by co-immunoprecipitation, that cyclin M interacts with SALL1 but not with SALL4, and that reducing its expression by RNA interference decreases the proliferation of HEK293 cells [7]. The function of this interaction with the Townes-Brocks syndrome protein remains unknown [5].

2.3. From enzyme deficiency to phenotype

STAR syndrome variants are loss-of-function variants: deletions of exons or of the whole gene, splice-site variants and frameshift variants [5]. Absence of cyclin M increases ETS2 levels, and transgenic mice overexpressing Ets2 have cranial and skeletal defects, suggesting that part of the syndrome's morphology results from this excess [5]. The second proposed pathway is ciliary: deficiency of CDK10 or cyclin M disorganises the actin network through loss of PKN2 phosphorylation and RhoA stabilisation, and favours the assembly and elongation of primary cilia; forced expression of RhoA reverses this effect [31]. Dilated tubules and elongated cilia were observed in a patient's kidney biopsy [31]. Renal, retinal and digital anomalies, frequent in ciliopathies, support the hypothesis, which remains based mainly on cellular models [5].

2.4. X-linked dominant inheritance, X inactivation and the male sex

STAR syndrome is transmitted as an X-linked dominant trait, and all published patients are female [9, 11]. Unger and colleagues found complete or near-complete skewing of X inactivation in all the patients studied, and Boone and colleagues confirmed complete skewing in a seventh patient [9]. The proposed interpretation is that cells in which the X carrying the variant remains active have a proliferative disadvantage during development, in keeping with the reduced proliferation observed in vitro [5, 9]. The absence of affected males and this cellular selection lead the authors to consider male lethality probable, but there is no direct demonstration, such as documented male fetal losses, in the sources consulted [5, 9, 13]. Skewed X inactivation does not by itself explain the variable severity: patients with similar variants differ in the extent of malformations, and carrier mothers may have only syndactyly [10, 16].

2.5. Variant spectrum and normalisation

ClinVar records for CCNQ consulted on 31 October 2026 numbered 342, with 75 classified as pathogenic and 4 as likely pathogenic [34]. Most of these pathogenic records are large copy-number variations of the long arm of the X, such as terminal Xq deletions or Xq28 duplications including MECP2, classified under the disease of the neighbouring gene and not under STAR syndrome [34]. The variants described in patients with the syndrome were normalised in VariantValidator and ClinVar on transcript NM_152274.5; the 2008 designations rest on an earlier annotation, shifted by 102 nucleotides (34 codons), and VariantValidator rejects them on the current transcript [34, 35].

ClinVar also contains NM_152274.5:c.655C>T p.(Gln219Ter), pathogenic, and NM_152274.5:c.193_196dup p.(Ala66GlyfsTer4), likely pathogenic, submitted without a detailed phenotype [34]. Truncating variants located at the end of the coding region deserve comment. c.651G>A p.(Trp217Ter) removes the last 32 amino acids and should not undergo nonsense-mediated messenger RNA decay; in vitro, the truncated cyclin forms a heterodimer with CDK10 and retains about 40% of kinase activity, but in human cells it is partially degraded in the proteasome, pointing to partial loss of function [33]. The variants c.535del and c.502_518delinsA shift the reading frame and extend the protein with an abnormal carboxy-terminal tail; for the second, the authors described reduced cyclin M expression and, unexpectedly, greater affinity of the mutant complex for CDK10 [11, 14]. No founder variants have been described.

2.6. Contiguous deletions and extended phenotypes

About half of the patients in the initial series had deletions, and other deletions, ranging from a single exon to 150 kb, were found later [3, 9, 13]. Many of the additional signs, including those of the only lethal form described, occurred in patients with deletions extending beyond CCNQ, and loss of neighbouring genes is suspected to contribute to the extended phenotype [5]. The patient of Bedeschi and colleagues, with a 130 kb deletion at Xq28, had cleft lip and palate, omphalocele and brain malformations and died at 6 weeks of respiratory failure, a picture the authors called "STAR plus" [4]. In the patient of Li and colleagues, the 150 kb deletion encompassed six genes and the authors considered that the retinopathy might be due to a contiguous gene, although none of the other five had a known ocular association [13]. Larger Xq deletions extending to MECP2 or other Xq28 genes belong to other entities and are not classified as isolated STAR syndrome [34].

2.7. Genotype-phenotype correlation, penetrance and mosaicism

The number of patients does not allow statistical genotype-phenotype correlations. Expressivity is variable within families: in the Boczek family, mother, daughter and maternal half-sister shared the variant and differed in severity, and in the Che twins one had end-stage kidney disease and the other a milder phenotype [14, 16]. In families with maternal mosaicism, the mother had only bilateral 4–5 syndactyly with about 50% of cells carrying the deletion, or was asymptomatic [10, 14]. By 2020, four mother-daughter pairs had been described; the remaining variants were sporadic [5]. A carrier may therefore have minimal manifestations, which precludes speaking of incomplete penetrance without targeted examination of the feet, perineum and kidneys.

2.8. Related disease: Al Kaissi syndrome (CDK10)

Biallelic loss-of-function variants of CDK10 (OMIM gene 603464) cause Al Kaissi syndrome (OMIM 617694), which is autosomal recessive [5, 33]. Windpassinger and colleagues described nine patients from five families with severe growth delay, spinal malformations, facial dysmorphism and developmental delay, and Cdk10-null mice that died after birth with growth delay, skeletal defects and renal and pulmonary changes [6]. A patient homozygous for NM_052988.5:c.870_871del p.(Trp291AlafsTer18) in CDK10 had agenesis of the corpus callosum, sensorineural hearing loss, retinitis pigmentosa, vertebral anomalies, patent ductus arteriosus and facial dysmorphism reminiscent of STAR syndrome [26]. This variant was found in 36 of about 141,000 gnomAD genomes, almost all of Ashkenazi Jewish ancestry, with a carrier frequency of about 1 in 290 in that community [5]. The differences between the two syndromes, with intellectual disability and severe growth delay only in Al Kaissi syndrome, suggest functions of each subunit outside the complex or compensation by other cyclins [5].

The CDK10 gene lies at 16q24.3, on the plus strand, and the MANE Select transcript NM_052988.5 has 13 exons and encodes the 360-amino-acid isoform (NP_443714.3) [6, 36]. Four alternative transcripts have been described, differing in the untranslated regions and in exon 11; besides the full-length isoform, only the 272-amino-acid isoform (NM_052987.3) appears functional, but it lacks the ATP-binding domain and is expected to be catalytically inactive [6]. For years CDK10 was an "orphan" kinase, cloned by homology with CDK1, until cyclin M was identified as its activating subunit; the complex phosphorylates ETS2 and PKN2 [6, 30, 31]. Before the syndrome, the locus had been associated with stature in a genome-wide association study in Han Chinese, and cdk10 knockdown in zebrafish impaired neurogenesis [6].

The following table brings together the published variants, normalised in VariantValidator to the MANE transcript; all single-nucleotide variants and small deletions match the authors' original numbering, which used NM_052988.4 or NM_052988.5 [35].

The mechanism is loss of function. In the Windpassinger families, the patients' fibroblasts had less CDK10 messenger RNA, consistent with nonsense-mediated decay, and increased levels of ETS2, a substrate that CDK10 phosphorylates and targets for degradation [6]. The proliferation of these fibroblasts and of Cdk10-null mouse embryonic fibroblasts was normal, which led the authors to attribute the growth delay to developmental defects rather than to a cell-autonomous requirement of the kinase for division [6]. The c.870_871del variant, located in exon 11, escapes RNA decay and would allow translation of a 307-amino-acid protein lacking the bipartite nuclear localisation signal; in vitro, this CDK10 forms a heterodimer with cyclin M but has activity below 20% of normal, indistinguishable from that of a catalytically dead kinase, and in human cells it is markedly degraded in the proteasome [33]. The authors concluded that the Al Kaissi patient has total loss of complex activity, whereas STAR patients with the c.651G>A p.(Trp217Ter) variant in CCNQ retain partial activity [33].

The murine model reproduces part of the phenotype. Mice with deletion of exons 2 to 8 of Cdk10 were born at less than 6% of the expected rate, despite being present in Mendelian proportion at embryonic day 17.5, and almost none survived the first day; they had growth delay, bifid atlas or axis, absence of a mineralised odontoid process, reduced mineralised matrix of the skull and long bones, tubulonephrosis with 30% to 50% of tubules degenerate or necrotic, and pulmonary atelectasis [6]. Transcriptome analysis of eight tissues found 609 genes with altered expression in at least two tissues, about one third linked to metabolism, especially lipid metabolism (for example, HMGCS2, LIPA and LIPJ), and deletion of the gene in adult mice had no apparent effect, which places the requirement for CDK10 in development [6]. In a model with osteoblast-restricted deletion, loss of Cdk10 reduced osteoblast proliferation, bone formation and osteocalcin (Bglap) expression, with trabecular and cortical osteoporosis without change in osteoclasts [39].

The role of primary cilia remains to be clarified. Cdk10-null mouse embryonic fibroblasts formed longer cilia, as did cells with CDK10 or CCNQ knockdown, and the fibroblasts of the Windpassinger patients had altered expression of ciliary genes (BBS4, CEP290 and RPGRIP1L) [6, 31]. The fibroblasts of the Ashkenazi patient, in contrast, formed fewer and shorter cilia, although electron microscopy of nasal cilia and exhaled nitric oxide were normal [26]. This patient's retinitis pigmentosa, sensorineural hearing loss and agenesis of the corpus callosum support classification as a ciliopathy, but the direction of the ciliary defect differs between models and the number of patients studied is small [5, 26]. The resemblance to STAR syndrome is partial: in the Windpassinger comparison, spinal malformations, developmental delay and intellectual disability are specific to Al Kaissi syndrome, growth delay is more severe, and toe syndactyly and anogenital and renal malformations are rare [6]. The hypotheses put forward for this difference are the different nature of the variants and the existence of other CDK10 partners besides cyclin M [5, 6].

3. Clinical Spectrum and System-Specific Manifestations

3.1. What the published series measure

There is no STAR syndrome cohort: clinical knowledge derives from case and family reports published between 1996 and 2025. The cumulative number of patients varies with the date and with each author's criterion: Boczek and colleagues presented patients 11 to 13 in 2017, Robert and colleagues counted 12 patients in 2021, Li and colleagues 15 in 2022, and Zgheib and colleagues considered their 2025 patient the 19th case, after 18 female patients [11, 13, 16, 33]. GeneGuidance aggregate frequencies, imported from an earlier curation, classify as frequent (30–79%) toe syndactyly, anal atresia, fifth-finger clinodactyly, short stature, hypoplasia of the labia, vesicoureteral reflux and a lop ear, and as occasional (5–29%) renal failure, horseshoe kidney, ectopic kidney and renal agenesis; with fewer than 20 patients, these percentages describe the published set and not the affected population [2]. The following table brings together the patients with an accessible description in the sources consulted.

3.2. Feet and hands

Cutaneous toe syndactyly is constant and variably involves toes 2 to 5, often asymmetrically: in the Green family, 3–5 on one side and 4–5 or 2–5 on the other [3]. In the Zgheib patient, radiographs showed bilateral postaxial syndactyly of toes 2 to 5, agenesis of the third metatarsal and proximal and distal polydactyly of the fourth ray on the right, a sign not previously described [11]. Syndactyly of the hands is less common (fingers 4 and 5 of one hand in the same patient), and fifth-finger clinodactyly, fifth-finger nail dysplasia, single palmar creases and persistent fetal fingertip pads have been described [3, 11]. Bilateral clubfoot and a "ball-and-socket" ankle dysplasia occurred in individual patients [3, 13].

3.3. Face

Telecanthus, lateral displacement of the inner canthi and lacrimal puncta that is distinguished from true hypertelorism because the interpupillary distance is not increased, and the broad, trifid nasal tip form the facial pattern [1, 3, 41]. The nasal root may be depressed or flat, and the ears low-set, with an overfolded upper helix or lop ears [2, 3, 11]. In the Green family the mother had a narrow nose, which shows variation within the same family [3]. Cleft lip and palate has been described only in the form with an extended deletion [4].

3.4. Anorectal region and genital tract

Anorectal malformation is one of the criteria that give the syndrome its name and ranges from anal stenosis to imperforate anus, with anteriorly placed anus, rectovaginal or anovaginal fistula and, at the extreme, common cloaca [3, 9, 13]. Clitoromegaly is frequent and may amount to ambiguous genitalia at birth; hypoplasia of the labia is part of Unger's definition [3, 9]. Urogenital sinus and bicornuate uterus have been described [3, 12]. In a group of 45 newborns with anorectal malformation treated in Palermo between 2009 and 2020, one girl had an Xq28 deletion inactivating the gene, and the authors concluded that the syndrome should be part of the differential diagnosis in girls with anorectal malformation [40]. The same conclusion appears in the title of a 2015 report [42].

3.5. Kidney and urinary tract

Renal malformations include solitary or ectopic pelvic kidney, horseshoe kidney, agenesis, unilateral or bilateral hypoplasia and hydronephrosis, and vesicoureteral reflux is frequent [2, 3, 12]. Chronic kidney disease may appear in childhood or adulthood: one of the Che twins progressed to end-stage kidney disease, the Lefroy woman had reduced renal function at 19 years, and the Orge mother learned of her hypoplastic kidney only at 19 years [3, 12, 14]. Acute pyelonephritis at 3 months due to grade 2 reflux in the Zgheib patient illustrates the early infectious complication [11]. Che and colleagues call the syndrome an X-linked "renal ciliopathy" [14].

3.6. Spine and central nervous system

Tethered cord was described in the three patients of the Boczek family, who proposed it as part of the phenotype, and in the Li patient, operated on at 3 months [13, 16, 33]. Syringomyelia occurred in Unger's patient 1 and in the Zgheib patient, and ventriculomegaly or hydrocephalus without need for shunting in two patients [7, 11, 13]. Vertebral anomalies include vertebral fusions, bifid posterior arch of C2, sacral spina bifida occulta and scoliosis, and a sacral dimple is frequent in recent descriptions [3, 9, 11, 14]. Epilepsy was recorded in one patient with a deletion [7]. Neurogenic bladder and bowel led to ileostomy and surgical revisions at 4 years in the Li patient [13].

3.7. Eye

Ocular involvement is varied. Besides telecanthus, lower eyelid coloboma, congenital ptosis, medial prominences of the upper eyelids with madarosis, bilateral Duane anomaly and accommodative esotropia have been described [3, 12, 13]. In the anterior segment, the daughter of the Orge pair had peripheral anterior synechiae without glaucoma at 6 months [12, 13]. In the posterior segment, Orge and colleagues described peripapillary atrophy, soft macular drusen and, in the daughter, optic nerve hypoplasia; Unger reported myopia of −5 dioptres with dystrophic retina and macular hypoplasia [12, 13]. Li and colleagues documented by multimodal imaging foveal hypoplasia, outer retinal atrophy with ellipsoid zone disruption and peripheral changes of the pigment epithelium in a radial pattern, suggestive of retinal degeneration, without knowing whether it is progressive [13]. The 2016 authors concluded that a complete ophthalmological examination should be part of the assessment [12].

3.8. Hearing

Hearing loss was described in the proband of the Boczek family, as left sensorineural hearing loss in the Li patient and in the more severely affected Che twin [13, 14, 16]. Boczek and colleagues proposed it as a sign of the syndrome [16].

3.9. Heart and other organs

Congenital heart disease is occasional: ventricular septal defect in the Green mother, atrial and ventricular septal defects in the Boone patient, unspecified heart disease in the Orge daughter, ventricular septal defect and ductus arteriosus with spontaneous closure in the Li patient, and minimal patent foramen ovale in the Zgheib patient [3, 9, 11–13]. Intestinal malrotation, accessory or supernumerary nipple, haemangioma, joint laxity and omphalocele (in the extended form) complete the spectrum [4, 5, 11, 13, 33].

3.10. Growth and neurodevelopment

All the patients in the Unger and Green series had growth delay, and short stature was noted in the founding family [5, 29]. The syndrome is not associated with neurodevelopmental delay or intellectual disability: intellect was normal in the 2008 series, development was normal in the Lefroy woman and psychomotor development was normal at 6 months in the Zgheib patient [3, 11]. Delays or cognitive deficits should prompt a search for an extended deletion or another cause [5].

3.11. Lethal form and extended phenotypes

The Bedeschi patient, with a 130 kb deletion including the gene, is the only published lethal form: cleft lip and palate, omphalocele and brain malformations, with death at 6 weeks from respiratory failure [4]. Its inclusion in the spectrum shows that the severity of deletions depends on the contiguous genes [5].

3.12. Prenatal period

The prenatal findings described are oligohydramnios, in two pregnancies (the Orge daughter and the Li patient), and unilateral pelvicalyceal dilatation at 37 weeks, not confirmed after birth, in the Zgheib patient [11–13]. In one pregnancy, the team discussed termination of pregnancy in mid-gestation because of a guarded prognosis, and the child survived; the mother recounted this experience in a neonatal nursing journal, with no genetic data in the abstract [43]. Anorectal malformations are diagnosed prenatally in fewer than half of cases [18].

3.13. Al Kaissi syndrome: clinical spectrum

The reference description remains that of Windpassinger and colleagues, who brought together, through GeneMatcher, nine patients (seven boys and two girls) from five families from Tunisia, Algeria, Saudi Arabia and Turkey, eight of them consanguineous, examined between 18 months and 9 years [6]. Mean height was −3 standard deviations (−1.3 to −4.5), mean weight −3.1 standard deviations (−0.2 to −4.7) and mean head circumference −2.2 standard deviations, with a range of −4.6 to +3 that includes one macrocephalic child [6]. All had developmental delay, with a mean age of sitting at 19 months (11 to 30) and of walking at 33 months (22 to 48), one non-ambulant child, marked language delay and moderate to severe intellectual disability [6].

The shared face is triangular, with a small, pointed chin, low-set and posteriorly rotated ears, a depressed or broad nasal root with a broad nasal tip, telecanthus (seven of nine) and epicanthic folds (nine of nine); downslanting palpebral fissures, a long, smooth philtrum, high-arched palate, macrodontia, glabellar naevus flammeus, malar erythema and strabismus were also described [6]. The hands are small, with fifth-finger clinodactyly and a single transverse palmar crease in some patients; there was joint hyperlaxity and flat feet, and a sacrococcygeal dimple in five of seven patients examined [6].

Cervical spine anomalies are the most characteristic sign. On skeletal survey, all patients studied except one had a cleft of the posterior arch of the atlas and partial fusion of C2 and C3; one patient also had severely abnormal cervical segmentation, another a T4 thoracic hemivertebra, non-fusion of the anterior arch of the atlas and of the posterior arches of S2 to S5 [6]. Later cases confirmed the pattern: C5–C6 fusion in a Chinese girl, C3–C4 dyssegmentation with a rudimentary coccyx and dermal sinus in the Ashkenazi patient, and spinal malformations in the two Turkish siblings [26, 27, 38]. Magnetic resonance imaging showed hypoplasia of the corpus callosum in three patients of the original series and near-complete agenesis with white matter rarefaction in the Ashkenazi patient [6, 26].

Later reports broadened the spectrum. The Ashkenazi patient had intrauterine growth restriction, birth weight of 1480 g (−3.7 standard deviations), heart failure due to patent ductus arteriosus operated on at 8 months, vocal cord paralysis with tracheostomy, gastrojejunostomy for vomiting and faltering weight gain, bilateral sensorineural hearing loss, retinitis pigmentosa with high myopia, absent expressive language, hyperactivity and muscle weakness with normal creatine kinase and muscle histology, without anogenital or renal malformations [26]. A 6-year-old Chinese boy had low-set, prominent ears, a triangular face, language and intellectual delay and a ventricular septal defect [37]. Hydrocephalus was described in a 4-year-old boy and in a 20-week fetus, with ventriculomegaly and irregular spinal alignment, whose pregnancy was terminated [28, 44]. The authors of the murine study with osteoblast deletion evaluated a family with a CDK10 variant: of the eight individuals, two had died and two were children; the three adults studied by densitometry had osteopenia, and a 73-year-old had vertebral fractures from T9 to T11 and of L5 [39]. The zygosity of each individual in this family is not described in the text of the article, which prevents separating the effect of the recessive disease from that of possible heterozygosity.

Abbreviations: SD, standard deviations; F, female; M, male; IUGR, intrauterine growth restriction. Blank dashes correspond to data not available in the parts of the articles consulted (for Beriwal and Sheikh, only the title and bibliographic data).

4. Clinical Recognition and Warning Signs

4.1. When to suspect

The Oxford Desk Reference summarises the suspicion in one sentence: think of STAR syndrome in a girl with toe syndactyly associated with renal and anogenital malformation, sometimes with telecanthus [45]. The typical presentation is neonatal: a newborn girl with imperforate anus, anal stenosis or fistula, clitoromegaly and toe syndactyly, in whom ultrasound reveals an ectopic, hypoplastic or absent kidney. Anal anomalies occur in about 4 per 10,000 births and two thirds are accompanied by other anomalies, so toe syndactyly and the facies should be sought in all girls with anorectal malformation [45]. Late presentation is possible: a woman with a single or hypoplastic kidney, a history of anorectal surgery and toe syndactyly, or the mother of an affected child with isolated syndactyly, who may be a mosaic carrier [10, 12].

4.2. Signs pointing to another entity

STAR syndrome is much less frequent than its differentials. A boy with the same picture and involvement of the thumb or the external ears point first to Townes-Brocks syndrome; radial anomalies and tracheo-oesophageal fistula, especially combined with hemivertebrae and heart disease, to the VACTERL association; intellectual disability, to an extended deletion or another syndrome [3, 5, 45]. These pointers are not mutually exclusive, and the Zgheib patient was also tested for SALL1, SALL4 and MYCN [11].

4.3. Urgent situations

The emergencies of the neonatal period are those of anorectal malformation: failure to pass meconium with intestinal obstruction, cloaca with hydrocolpos and obstructive uropathy, associated heart disease and urinary infection in a malformed urinary tract [18, 19]. The European guideline calls for diagnosis of the malformation within the first 24 to 48 hours of life and for an immediate search for potentially lethal comorbidities, especially cardiac ones [18, 19]. Later, febrile urinary infection in a child with reflux requires immediate parenteral antibiotic treatment, and deterioration of continence or motor function may indicate tethered cord [18, 20].

4.4. Newborn screening

There is no biochemical or molecular newborn screening for the syndrome. Detection depends on examination of the newborn and on the assessment of anorectal malformations [18].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

No validated formal diagnostic criteria exist. The operational definition remains that of Unger and colleagues: facies with apparent telecanthus and a broad, trifid nasal tip, variable syndactyly of toes 2 to 5, hypoplastic labia, anal atresia and urogenital malformations, in a patient with normal intellect [3]. In the published reports, all patients share these elements, with variable expressivity, and the diagnosis is confirmed by the CCNQ alteration [11]. Absence of one of the signs does not exclude the syndrome in a carrier of a familial variant, because carrier mothers may have only syndactyly [10].

5.2. Clinical assessment and orientation investigations

The assessment of a girl with anorectal malformation follows the general principles for these malformations. The Oxford Desk Reference advises a three-generation pedigree with questions about neonatal surgery and colostomy, a history of maternal diabetes, photography of the anus and genitalia before surgery, examination of the external ear, heart and limbs, radiographs of the spine, sacrum, pelvis and chest, lumbosacral magnetic resonance imaging (MRI), renal ultrasound and echocardiography, because urogenital and cardiovascular anomalies account for 49% and 27% of associated anomalies [45]. The ERN eUROGEN guideline adds classification of the malformation type by the Krickenbeck classification, a targeted search for the anomalies of the VACTERL association, urinary and spinal canal ultrasound in the first weeks, assessment of the internal genitalia by cystovaginoscopy or MRI before or during reconstruction, and a genetics clinic referral, strongly recommended when there is at least one additional anomaly [18]. In STAR syndrome, a complete ophthalmological examination and audiological assessment are justified by the findings described [12, 13, 16].

5.3. Molecular testing: choice and sequence

The syndrome results from point variants and deletions in similar proportions: in the initial series, two of the four index patients had deletions and were diagnosed by array CGH, and the deletions published since range from one exon to 150 kb [3, 9, 13]. The strategy must therefore detect both classes. One option is chromosomal microarray analysis, suited to deletions of several tens of kb or larger, followed by sequencing of CCNQ or a panel; the other is exome or genome with copy-number variant analysis [9, 11]. The 2021 American College of Medical Genetics and Genomics (ACMG) guideline strongly recommends considering exome or genome sequencing as a first- or second-tier test in children with one or more congenital anomalies with onset before 1 year, because of the higher yield and possible cost-effectiveness when ordered early [17]. In a clinical database of about 17,000 exomes, 45 of 130 children with syndromic anorectal malformation (34.6%) received a definitive or probable diagnosis; the yield was 26.8% in those meeting VACTERL criteria and 44.1% in the remainder (p = 0.0437), and the authors recommend exome sequencing in all undiagnosed syndromic anorectal malformations [46]. In kidney disease, the 2022 European recommendations state that a monogenic cause is found in 10–15% of congenital anomalies of the kidney and urinary tract (CAKUT), even with massively parallel sequencing, and that copy-number variations require targeted or validated methods [47].

5.4. Limitations of the tests

A microarray of usual clinical resolution may not detect an intragenic deletion: the 8–10 kb deletion including exon 5 was identified only on an array with exonic probes, and the initial series also used quantitative PCR (qPCR) [9, 15]. Exome sequencing detects point variants and small insertions and deletions, but detection of single-exon deletions depends on the copy-number variant calling algorithm and on coverage; a negative exome does not exclude the syndrome in the face of a typical phenotype [47]. Deep intronic splicing variants, inversions and balanced rearrangements have not been described, and the sources do not allow their frequency to be assessed. In parents, mosaicism may go unnoticed: Lefroy's mother had about 50% of cells with the deletion and the mother of the Che twins was asymptomatic, and detection requires blood analysis with sufficient sensitivity or analysis of other tissues [10, 14]. The proportion of variants detectable by each method is not to be confused with clinical sensitivity, which has not been estimated.

5.5. Report and interpretation

The report should state the gene (CCNQ, mentioning the old symbol FAM58A to facilitate literature searches), the transcript and version (NM_152274.5), the HGVS (Human Genome Variation Society) designation in c. and p. forms, the zygosity (heterozygous), the origin when known, the class according to ACMG/AMP (Association for Molecular Pathology) criteria and, for deletions, the coordinates, genome build and genes included [11, 13]. Zgheib and colleagues classified the c.535del variant as pathogenic by combining PVS1 at strong strength (frameshift producing a longer protein), PS2 (de novo) and PM2 (absent from gnomAD) [11]. In contiguous deletions, the list of genes included guides the assessment of additional signs [5, 13]. Variants of uncertain significance in CCNQ are numerous in ClinVar (43 in October 2026), and family segregation, de novo origin and phenotypic concordance are the elements that allow them to be reclassified [34, 47].

5.6. Practical algorithm

5.7. Prenatal and preimplantation diagnosis

Ultrasound signs are non-specific (oligohydramnios, urinary tract dilatation, suspected anorectal malformation), and the syndrome cannot be diagnosed prenatally from isolated signs [11–13, 18]. With a known familial variant, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are technically possible; the sources consulted do not describe cases in which they were used. Interpretation of a positive result in a female fetus does not allow severity to be predicted, given the familial variability [14, 16].

5.8. Al Kaissi syndrome: diagnosis

There are no formal clinical criteria. Suspicion rests on the combination of severe short stature of prenatal onset, intellectual disability, facial dysmorphism with a triangular face, telecanthus and posteriorly rotated ears, and cervical spine anomalies (cleft of the posterior arch of the atlas, C2–C3 or other segmental fusion), which should be sought by spinal radiography or MRI in any child with this picture [6, 38]. Routine endocrine studies do not distinguish the syndrome: in the Chinese girl the stimulated growth hormone peak was 10.61 ng/ml, insulin-like growth factor 1 (IGF-1) −1.2 standard deviations and karyotype 46,XX, and in the Ashkenazi patient an extended metabolic work-up was normal [26, 38].

The first-line test is exome or genome sequencing, with copy-number variant analysis, because two of the 12 published families have homozygous exon deletions [6, 17, 37]. In the Chinese child with a homozygous deletion of exons 1 and 2, low-coverage sequencing for copy-number variations was normal and the deletion was identified only by exome analysis, with confirmation by PCR and quantitative PCR [37]. In the Chinese fetus, the first exome reading identified no relevant variants, and the diagnosis emerged only on targeted reanalysis of both CDK10 alleles, confirmed by segregation in the parents and siblings and by functional studies [28]. An isolated heterozygous variant in a child with a suggestive phenotype requires a search for a second allele by deletion/duplication analysis and, if necessary, by RNA studies, because splicing variants (NM_052988.5:c.608+1G>A, c.609-1G>A and c.933-2A>G) are frequent in the spectrum [6, 28]. The Xue preprint classified the missense variant NM_052988.5:c.663C>G p.(Asp221Glu) as of uncertain significance, in compound heterozygosity with a nonsense variant; in that family, attribution of the diagnosis rests on phenotypic concordance and segregation, without functional studies [38].

The report should state the transcript NM_052988.5, both variants with zygosity, the phase (cis or trans) confirmed in the parents and the ACMG/AMP class [28, 35]. In prenatal diagnosis, hydrocephalus, ventriculomegaly and spinal anomalies are the findings described, without specificity [28]. With the familial variants known, diagnosis by chorionic villus sampling has already been used in a subsequent pregnancy, which revealed a heterozygous carrier fetus [37].

6. Differential Diagnosis

6.1. Comparative table

6.2. Townes-Brocks syndrome

This is the main differential, discussed already in the 1996 description, and some patients with STAR syndrome were first diagnosed as Townes-Brocks [5, 29]. The two share anorectal malformation, renal anomalies and foot anomalies; Townes-Brocks is distinguished by thumb involvement (triphalangeal, hypoplastic or duplicated), dysplastic external ears and autosomal dominant transmission, which includes affected males [3, 45]. The interaction between cyclin M and SALL1 suggests a common developmental pathway, without diagnostic significance [5, 7]. SALL1 testing was negative in the patients of the initial series and in the 2025 patient [3, 11].

6.3. VACTERL association and syndromic anorectal malformations

The VACTERL association combines vertebral defects, anal atresia, heart disease, tracheo-oesophageal fistula with oesophageal atresia, renal anomalies and limb defects, with an incidence of 1.6 per 10,000; the limb defect is preaxial and radial, and the lower limbs are not affected [45]. In STAR syndrome, the limb anomaly is toe syndactyly, and tracheo-oesophageal fistula has not been described in the sources consulted. VACTERL is a diagnosis of exclusion, and the exome yield is lower in children meeting its criteria (26.8%) than in other syndromic anorectal malformations (44.1%) [46].

6.4. Okihiro, Feingold and Al Kaissi

Okihiro and Feingold syndromes were studied because of overlap with STAR [3]. Feingold syndrome is the differential in which the toe syndactyly is most similar, with typical fusion of toes 2/3 and 4/5, but it is accompanied by microcephaly, brachydactyly of the hands, short palpebral fissures, learning difficulties and digestive atresias, and it affects both sexes [49]. In Okihiro syndrome, Duane anomaly is associated with defects of the radial ray and thumb and with crossed renal ectopia [48]; the bilateral Duane anomaly of the Lefroy patient shows that the ocular sign also occurs in STAR [3]. Al Kaissi syndrome results from loss of the other subunit of the CDK10/cyclin M complex, but severe growth delay, spinal malformations and intellectual disability dominate the picture, and inheritance is autosomal recessive [5, 6].

6.5. Other causes of anorectal malformation

Opitz G/BBB syndrome, Currarino syndrome, Mabry syndrome, caudal regression and the OEIS complex (omphalocele, cloacal exstrophy, imperforate anus and spinal defects) enter the general differential of anorectal malformations [45]. In the exome study of syndromic anorectal malformations, diagnoses included variants in ADNP, BBS1, CREBBP, EP300, FANCC, KDM6A, SETD2 and SMARCA4 [46]. In a girl, STAR is distinguished by toe syndactyly, the facies and cognitive integrity.

7. Treatments and Risk Management Strategies

7.1. General principles

There is no treatment targeting cyclin M deficiency, nor a guideline specific to STAR syndrome. Management is that of each malformation and rests on the 2025 ERN eUROGEN anorectal malformation guidelines, developed with experts from ERNICA and the European Paediatric Surgeons' Association (EUPSA), the 2026 European Association of Urology (EAU) paediatric urology guidelines and the European recommendations for genetic testing in kidney disease [18–20, 47, 50]. The ERN eUROGEN guidelines resulted from adaptation, by the ADAPTE method, of the 2020 Dutch quality standard for anorectal malformations, by a 15-member panel from 7 countries with two patient representatives; the network brings together 56 providers from 20 countries and about 12,500 patients per year, and most recommendations are based on retrospective studies, case series or expert opinion (grade D) [18]. The child should be followed by a multidisciplinary team with paediatric surgery, paediatric urology and nephrology, gynaecology, neurosurgery, ophthalmology, audiology and genetics [18, 50].

7.2. Anorectal malformation: neonatal period and reconstruction

The newborn girl should be referred to paediatric surgery as soon as the malformation is recognised, and within the first 24 hours the passage of meconium, the type of malformation and potentially lethal comorbidities, especially heart disease, are assessed [19]. Without sufficient passage of meconium, initial management includes venous access, a nasogastric tube, withholding feeds and intravenous antibiotics, followed as a rule by a three-stage approach: colostomy, reconstruction and stoma closure [19]. The colostomy may be a loop or divided colostomy, with no evidence favouring either technique, although the loop may have more prolapse [19]. Complex malformations, such as cloaca, should be treated in a reference centre [19]. Reconstruction should be performed in the first year of life if there is no contraindication, and the technique (anoplasty, anterior or posterior sagittal anorectoplasty, laparoscopic pull-through) depends on the type and on local experience, with no demonstrated superiority of any [19]. Before reconstruction, the type according to the Krickenbeck classification and the anatomy should be characterised by high-pressure distal colostogram, MRI or cystoscopy [18].

7.3. Anorectal malformation: postoperative care and continence

The perineum and neo-anus are reassessed up to 3 weeks after surgery, with painless calibration [18]. Routine anal dilatations are not mandatory; when performed, they should not be painful or continue beyond 3 to 4 months, and late cutaneous stenosis can be treated by dilatation under anaesthesia or by strictureplasty [19]. Toilet training can begin between 2 and 5 years, with an individual protocol [19]. Constipation with overflow incontinence should be recognised by the parents; faecal incontinence is treated with enemas, rectal irrigation or oral laxatives when there is constipation, with antegrade irrigation through a Malone stoma if rectal irrigation fails and, as a last resort, a permanent stoma [19]. The perineal skin requires care with sitz baths, zinc oxide ointments and barrier creams [19]. The medicines used in this management (laxatives, enemas) are in common use, with no dosing specific to the syndrome.

7.4. Kidney and urinary tract

Renal and bladder ultrasound is performed in the first weeks, and children with urological problems (recurrent infections, post-void residual, reduced renal function, absent spontaneous voiding, bladder dysfunction) are referred to paediatric urology; urodynamic studies are reserved for children with symptoms of lower urinary tract dysfunction [18]. For vesicoureteral reflux, the EAU recommends, among other measures, initial continuous antibiotic prophylaxis in all symptomatic children diagnosed in the first year of life, regardless of grade and scarring (weak recommendation), and surveillance without prophylaxis in low grades without symptoms (strong) [20]. The most commonly used agents are trimethoprim-sulfamethoxazole, amoxicillin and nitrofurantoin, at a quarter to a half of the therapeutic dose; febrile breakthrough infection is treated immediately by the parenteral route (strong) [20]. Surgical (reimplantation) or endoscopic correction is proposed in the presence of frequent breakthrough infections (weak), persistent high-grade reflux with reimplantation and low grades with endoscopy (strong), children over 1 year with high grade and abnormal parenchyma (weak) or parental preference (strong); in children with established renal damage, the approach should be multidisciplinary and more aggressive (strong) [20]. Lower urinary tract dysfunction should be sought in all children and treated first, and parents should know that siblings and offspring have a high prevalence of reflux (strong) [20]. This last recommendation refers to primary reflux; in STAR syndrome, the risk to siblings depends on the inheritance (section 8). Chronic kidney disease, described at end stage in one patient, follows the usual nephrological treatment, including dialysis and transplantation, on which the sources for the syndrome provide no specific data [14].

7.5. Spine and nervous system

All children with anorectal malformation should be screened for spinal dysraphism, with spinal canal ultrasound in the first month of life (later, closure of the vertebral arches prevents assessment) and radiographs of the spine and sacrum [18]. In the presence of neurological signs or vertebral, sacral or spinal canal anomalies, the child is seen by paediatric neurology and may have MRI before 12 months; the onset or worsening of symptoms (loss of continence, sensorimotor change) requires reassessment by neurology or neurosurgery [18]. Tethered cord, described in at least four patients, was released at 3 months in the Li patient [13, 16]. The syringomyelia and hydrocephalus described did not require shunting in the reports [11, 13].

7.6. Genital tract and gynaecology

The external and, whenever possible, internal genitalia should be assessed and documented before or during reconstruction, by cystovaginoscopy or MRI, and genitourinary anomalies are treated by a team that includes paediatric gynaecology [18]. Hydrocolpos may cause obstructive uropathy and is more likely in cloaca [18]. Gynaecology follows the patient throughout life, with anatomical assessment before puberty, prevention of vaginal stenosis and counselling at puberty in patients with a reproductive tract malformation; if there are complaints in adolescence, pelvic ultrasound around menarche looks for retained menstrual blood [18, 50]. The sources do not describe the treatment of clitoromegaly in patients with STAR.

7.7. Eye, hearing, heart and limbs

A complete ophthalmological examination is recommended by the authors of the ocular reports, with prolonged retinal follow-up given the changes described [12, 13]. Hearing loss, described in three patients, requires audiological assessment and rehabilitation according to type and degree [13, 14, 16]. Heart disease is treated by paediatric cardiology; in the reports, the ventricular septal defect and ductus arteriosus closed spontaneously [13]. The sources do not describe surgical correction of toe or finger syndactyly or of polydactyly in patients with the syndrome [11].

7.8. Information, support and autonomy

Parents should receive, from surgeons and nurses and repeatedly, information about the disease, postoperative care, constipation, the risk of incontinence and the possibility of several operations, together with contact details of patient organisations; a 24-hour contact and a care plan with documented and reviewed goals should be available [19]. Mental health and psychosocial well-being should be addressed, and neuropsychological follow-up is recommended in the presence of poor school performance or difficulty concentrating, because people with anorectal malformation have more developmental disorders, anxiety, depression and hyperactivity than their peers [50].

7.9. Regulatory status, trials and new developments

The ClinicalTrials.gov search of 31 October 2026 with the terms CCNQ, FAM58A, "STAR syndrome" and "syndactyly telecanthus" returned no studies, and there is therefore no trials table. The literature search from 1 October 2025 to 31 October 2026 found no new clinical reports of the syndrome; the most recent report, by Zgheib and colleagues, appeared in 2025 and added polydactyly of the feet and supernumerary nipple to the spectrum [11]. In the same period, work on CDK10 was preclinical (bone formation, cancer) or reports of Al Kaissi syndrome, with no consequence for the treatment of STAR. A negative search does not prove the absence of non-indexed studies.

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

The sources do not identify drugs contraindicated by the syndrome. In the pregnancy of a woman with an operated anorectal malformation, the European guideline calls for follow-up by a gynaecologist experienced in the malformation and access to a paediatric surgeon with that experience, preconception examination of the perineum and close surveillance; vaginal delivery is possible, but caesarean section should be strongly considered if there is doubt and offered to those who wish it [18]. The sources for the syndrome provide no data on pregnancy outcome in affected women, nor on specific perioperative care. Transition to adult care is planned from 12 to 14 years and should be completed before 18, under the responsibility of the paediatric centre, with coordination between paediatric and adult specialists [50].

7.11. Al Kaissi syndrome: treatment and management

There is no targeted treatment or specific guideline, and management is supportive: assessment of growth, the cervical spine, neurodevelopment, hearing, vision and the heart, according to each child's findings [6, 26]. The Ashkenazi patient received growth hormone from 2 years of age, with a response described as favourable and height at the 5th centile at 11 years; this is the only published treatment report, with no dose stated and no comparison group [26]. The syndrome is not an authorised indication for somatropin. In children with intrauterine growth restriction and persistent short stature, such as the Ashkenazi patient, the closest reference is the indication for children born small for gestational age, and the following dose is an extrapolation from that condition [51, 52].

Scoliosis and vertebral anomalies weigh on the decision: the somatropin SmPC notes that rapid growth may worsen scoliosis, which justifies radiological assessment of the spine before starting and during treatment [6, 52]. The relationship between CDK10 deficiency and osteopenia in the adults of one family studied by densitometry, with vertebral fractures in a 73-year-old, suggests monitoring bone mineral density in adulthood and correcting osteoporosis risk factors, although the data are limited to three densitometry scans [39]. Windpassinger's hypothesis that ETS2 inhibition or dietary intervention on the lipid metabolism changes might attenuate the disease has not gone beyond the hypothesis stage, and there are no studies in patients [6]. The ClinicalTrials.gov search of 1 November 2026 with the terms CDK10 and "Al Kaissi" returned no trials for the syndrome, and the 2025–2026 publications on CDK10 are case reports, a prenatal functional study and preclinical work on bone formation and cancer [27, 28, 39].

Cervical spine anomalies (cleft of the posterior arch of the atlas, absence of a mineralised odontoid process in the murine model, fusions) call for radiological assessment before general anaesthesia, intubation or activities with a risk of cervical trauma, and coordination with orthopaedics; the sources do not describe cases of atlantoaxial instability or spinal cord injury [6]. The Ashkenazi patient required cardiac surgery, tracheostomy and gastrojejunostomy in the first year, which shows that the severely affected child needs a multidisciplinary paediatric team [26]. Intellectual disability and language delay call for early intervention, speech and language therapy and educational support; sensorineural hearing loss and retinitis pigmentosa, when present, follow the usual auditory and visual rehabilitation [6, 26].

8. Reproductive Options and Family Counselling

8.1. Recurrence risk

Most variants arise de novo, and by 2020 only four mother-daughter pairs had been published [5]. When the patient is the first in the family and the parents do not have the variant in blood, the risk to siblings is low but not zero, because maternal mosaicism has already been documented in two families and gonadal mosaicism is possible [5, 10, 14]. When the mother is a carrier, each pregnancy has a 50% probability of transmitting the X carrying the variant; daughters who inherit it will be affected with unpredictable severity, and in sons the lethality hypothesis makes pregnancy loss more likely than the birth of an affected boy, although the sources do not quantify the risk of miscarriage [5, 9]. An affected woman has, by the same reasoning, a 50% probability of transmitting the variant in each pregnancy [5]. In the Boczek family, a woman transmitted the variant to two daughters by different fathers, and in the Green family the mother transmitted it to her daughter [16, 29].

8.2. Testing of parents and relatives

Testing of the mother should use methods that detect mosaicism and be accompanied by examination of the feet, perineum and kidneys, because the Lefroy mosaic carrier had only bilateral 4–5 syndactyly and the mother of the Che twins was asymptomatic [10, 14]. Testing of the father serves mainly to confirm that the variant is de novo, given that no male carriers have been described [5]. The sisters and maternal aunts of a carrier may be tested for the same reason, after prior counselling.

8.3. Prenatal diagnosis, preimplantation testing and counselling

With the variant known, invasive prenatal diagnosis and preimplantation genetic testing are options to discuss with the family, bearing in mind that a positive result in a female fetus does not predict severity [14, 16]. The experience reported by one mother shows the weight, for the family, of a fatal prognosis conveyed during pregnancy for a child who ultimately survived, and advises care in how uncertainty is communicated [43]. Counselling should explain that intellect is usually normal and that morbidity depends on the anorectal, renal and spinal malformations, except in extended deletions [4, 11]. Testing of asymptomatic minor girls is performed when it has clinical consequences (for example, renal or ocular screening); testing for reproductive purposes should wait until the age at which the girl herself can decide.

8.4. Al Kaissi syndrome: counselling

Autosomal recessive inheritance gives the parents of an affected child, both carriers, a 25% risk in each pregnancy, a 50% chance of carrier children and a 25% chance of children with neither variant; healthy siblings have a two-thirds probability of being carriers [6, 28]. In the family of the Chinese fetus, the sister carried the paternal variant and the brother had neither variant [28]. Eight of the nine Windpassinger families were consanguineous, and consanguinity increases the risk in marriages within the extended family; in non-consanguineous families the diagnosis rests on compound heterozygosity, as in the Chinese and Turkish families, or on a variant frequent in one community, such as c.870_871del in Ashkenazi Jews [5, 6, 27, 38]. With the variants known, prenatal diagnosis by chorionic villus sampling and preimplantation genetic testing are options; the former has already been used [37]. The carrier frequency of about 1 in 290 for the c.870_871del variant in the Ashkenazi population, if confirmed, may justify its consideration in carrier screening panels for that community, but none of the sources consulted makes that recommendation [5].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

STAR syndrome belongs to the Orphanet prevalence class below 1 in 1,000,000, with worldwide distribution [2]. This class reflects the number of published cases, which was 19 female patients in 2025 according to Zgheib and colleagues, and does not result from a population study [11]. In a hospital series from Palermo, 1 of 45 newborns with anorectal malformation (2009–2020) had the syndrome; the number is too small to estimate the fraction of female anorectal malformations attributable to STAR [40]. Recognition may be underestimated, because the first patients were thought to have other syndromes and minimal forms in carrier mothers are identified only after a daughter's diagnosis [5, 10].

9.2. Geographical distribution of cases

The published patients come from the United Kingdom (the Green family and the Lefroy patient), Central and Western Europe (Unger's multicentre series), the United States (Boone, Zarate, Orge, Boczek, Li), Italy (Bedeschi, Schierz), China (the Che twins, the first Asian cases) and Switzerland (Zgheib) [4, 9–16, 29, 40, 42]. There are no founder variants or population clustering. The sources consulted do not include cases from Portugal or Brazil, which does not demonstrate that none exist.

9.3. Special populations

The male sex is the central special population: no affected male has been described, and a similar picture in a boy should point to other diagnoses [5]. Adult women with the syndrome may be unaware of the diagnosis until the birth of an affected daughter [10, 12].

9.4. European networks and patient organisations

ERN ITHACA is the European network for rare congenital malformations and intellectual disability and is the home for syndromic diagnosis [21]. ERN eUROGEN, for rare and complex urogenital diseases, produced the anorectal malformation guidelines [18, 22]. ERKNet covers rare kidney diseases and ERNICA rare congenital digestive anomalies, including anorectal ones [23, 24]. There is no patient organisation specific to the syndrome in the sources consulted; anorectal malformation organisations, such as the Pull-thru Network in the United States, serve families, and the European guideline recommends referral to them [19, 54].

9.5. Al Kaissi syndrome: epidemiology

Al Kaissi syndrome has no prevalence estimate; the sources consulted bring together about 18 individuals (17 born and one fetus) from 12 families up to 2026, and the 2026 prenatal study counted 13 published families [6, 26–28, 37, 38, 44, 55]. The families come from North Africa (Tunisia, Algeria), the Middle East (Saudi Arabia), Turkey, including one Kurdish family, Israel (Ashkenazi Jewish ancestry), India and China [6, 26, 27, 37, 55]. The only variant with a known population frequency is c.870_871del, found in 36 of about 141,000 gnomAD genomes, almost all Ashkenazi [5]. The frequency of the remaining variants in gnomAD is very low (0.000123 for NM_052988.5:c.613C>T) or zero [28]. The sources consulted do not describe patients in Portugal or Brazil.

10. Illustrative Clinical Case

10.1. Girl with an Xq28 deletion and retinopathy (Li and colleagues, 2022)

A girl was born at 37 weeks and 5 days, weighing 2550 g, by caesarean section for breech presentation, after a pregnancy complicated by oligohydramnios; the parents were not consanguineous and there was no family history [13]. At birth she had syndactyly of toes 3, 4 and 5 of both feet, telecanthus, imperforate and anteriorly placed anus, anovaginal fistula, bilateral hydronephrosis, tethered cord, left sensorineural hearing loss, clitoromegaly, an accessory nipple and bilateral clubfoot; investigations showed a ventricular septal defect and ductus arteriosus, which closed without intervention, and hydrocephalus that did not require shunting [13]. She underwent surgery at 3 months to release the cord, at 4 months to correct the anovaginal fistula, at 6 months for intestinal malrotation (laparoscopic Ladd procedure with appendicectomy), and at 4 years she had an ileostomy and several surgical revisions for neurogenic bladder and bowel [13].

Ophthalmological examination at 7 months showed mild telecanthus and mottled pigment at the macula, unchanged at 1 and 2 years [13]. At 5 years, corrected visual acuity was 20/200 in the right eye and 20/160 in the left, with cycloplegic refraction of −3.50 +4.50 × 95 and −3.25 +3.75 × 80, intraocular pressure of 14 and 15 mmHg and normal optic nerves [13]. Fundus photography showed yellow drusen-like deposits at the macula and peripheral changes of the retinal pigment epithelium, and autofluorescence revealed a radial pattern of hyperautofluorescence in the periphery (figures 1 and 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC8810370/figure/fig1/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC8810370/figure/fig2/) [13]. Optical coherence tomography showed outer retinal atrophy and ellipsoid zone disruption in both eyes, grade 1 foveal hypoplasia on the right and atypical foveal dysplasia on the left, and correlation with near-infrared imaging showed no true deposits beneath the pigment epithelium (figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC8810370/figure/fig3/) [13]. Optical coherence tomography angiography was normal and oral fluorescein angiography showed staining of the atrophic areas [13].

Chromosomal microarray analysis showed a 150 kb deletion, arr[hg19] Xq28(152,834,159–152,984,574)x1, with six genes, including FAM58A, classified as likely pathogenic; the parents did not have the deletion [13]. The authors interpreted the changes as possible outer retinal degeneration associated with the syndrome, compared the radial pattern with that of X-linked retinopathies and considered that a contiguous gene might contribute [13]. The case shows the accumulation of anorectal, urological, spinal and intestinal malformations that requires repeated surgery, and that retinal assessment can change the visual prognosis in a syndrome without intellectual disability. The surgical procedures described are those of this case and not a protocol.

10.2. Girl with a de novo variant and new signs (Zgheib and colleagues, 2025)

A girl was born at 39 weeks and 4 days, weighing 3010 g (17th centile), 51 cm long (43rd centile) and with a head circumference of 34 cm (27th centile), Apgar score 8-10-10, after an uneventful pregnancy apart from right pelvicalyceal dilatation at 37 weeks and 5 days, not confirmed after birth [11]. She had telecanthus, a flat nasal root, low-set ears with an overfolded upper helix, bilateral syndactyly of toes 2 to 5, syndactyly of fingers 4 and 5 of the left hand, a supernumerary nipple with the normal nipple displaced cranially and a sacral dimple; radiographs showed agenesis of the third metatarsal and proximal and distal polydactyly of the fourth ray of the right foot [11]. Spinal ultrasound and MRI showed syringomyelia, and brain MRI lateral ventricles of 11 and 10 mm; echocardiography revealed only a minimal patent foramen ovale [11]. Exome sequencing, with initial analysis restricted to CCNQ, identified the de novo variant NM_152274.5:c.535del p.(His179MetfsTer167), absent from population databases and classified as pathogenic; SALL1, SALL4 and MYCN were checked and had no variants [11]. At 3 months she had acute pyelonephritis due to grade 2 left vesicoureteral reflux confirmed by micturating cystourethrography, and at 6 months psychomotor development was normal [11]. The photographs (telecanthus, nipples, syndactylies and radiograph) and the pedigree are in figures 1 and 2 of the open-access article [11].

10.3. Girl with Al Kaissi syndrome and ciliopathy (Guen and colleagues, 2018)

The patient was the second daughter of healthy, non-consanguineous parents of Ashkenazi Jewish ancestry [26]. The pregnancy was complicated by intrauterine growth restriction, and the 32-week ultrasound showed agenesis of the corpus callosum; she was born at 39 weeks weighing 1480 g (−3.7 standard deviations) with a head circumference of 30.5 cm (−3.0 standard deviations) [26]. Shortly after birth, heart failure due to patent ductus arteriosus developed, surgically corrected at 8 months; after surgery, vocal cord paralysis was noted, leading to tracheostomy, and in the same month a gastrojejunostomy was placed for vomiting and faltering weight gain [26]. She started growth hormone at 2 years, with a favourable response [26].

In the second year of life global developmental delay became evident, without regression; she had a high forehead, mild bilateral ptosis, upslanting palpebral fissures, telecanthus, a broad nasal root and a long philtrum, without anogenital malformations (figure 1A of the article) [26]. Later investigations showed bilateral sensorineural hearing loss and retinitis pigmentosa with high myopia, with relatively preserved vision with glasses and no progression of the retinopathy [26]. Brain MRI at 6 years showed a rudimentary corpus callosum and white matter rarefaction around the posterior horns of the lateral ventricles (figures 1B and 1C), and spinal MRI, requested because of the dysmorphism, revealed C3–C4 dyssegmentation and a rudimentary coccyx with an adjacent dermal sinus [26]. Extended metabolic work-up, renal ultrasound, exhaled nitric oxide and electron microscopy of nasal cilia were normal [26].

At 11 years she weighed 31.3 kg (15th centile) and measured 131 cm (5th centile); she had no expressive language but understood simple commands, and cognitive development corresponded to severe intellectual disability, with marked hyperactivity and attention deficit; she walked with a wide-based, unsteady gait and had prominent weakness, with normal creatine kinase and muscle biopsy [26]. Exome sequencing identified the variant NM_052988.5:c.870_871del p.(Trp291AlafsTer18) in the homozygous state; the mutant RNA was not degraded, and the patient's fibroblasts, denser and less elongated than control fibroblasts, formed fewer and shorter cilia after serum starvation [26]. The face, compared by the authors with that of a STAR patient (figure 1D), illustrates the overlap between the two diseases of the CDK10/cyclin M complex, and the absence of anogenital and renal malformations and the severity of the intellectual disability illustrate the difference [6, 26]. The growth hormone treatment reported does not derive from a guideline for the syndrome and should not be read as routine.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

The vital prognosis is good in most of the patients described, who survived neonatal surgery and reached adulthood, like the mothers of the Green, Orge, Boczek and Lefroy families [10, 12, 16, 29]. The exception is the form with an extended deletion, lethal at 6 weeks [4]. Intellectual development is usually normal [3, 11]. Long-term morbidity depends on three domains: renal function, which may decline in adolescence or adulthood and reach end stage; faecal and urinary continence, compromised by the anorectal malformation and tethered cord; and vision, with possible retinal changes of unknown course [3, 13, 14]. In people with anorectal malformation in general, incontinence, chronic constipation and sexual dysfunction are frequent in adulthood and reduce quality of life [50]. The natural history of the syndrome at older ages has not been described.

11.2. Surveillance table

The sources do not define a surveillance protocol specific to the syndrome. The table brings together the indications of the guidelines for the components and the recommendations of the authors of the reports; where no source sets an interval, the frequency is individual.

11.3. Al Kaissi syndrome: prognosis and surveillance

The original series describes no deaths, and the patients were between 18 months and 9 years at examination; the Ashkenazi patient reached 11 years after cardiac surgery, tracheostomy and gastrojejunostomy, and the family studied by densitometry included adults, one aged 73, and two individuals who had died of unspecified causes [6, 26, 39]. Moderate to severe intellectual disability and short stature are permanent; experience with growth hormone is limited to one case [6, 26]. The intervals in the table derive from the published findings and the rules of the somatropin label; no source defines a specific protocol.

12. Summary and Final Considerations

STAR syndrome is an X-linked dominant malformation syndrome, described in about two dozen girls and women, which combines toe syndactyly, telecanthus with a broad nasal tip, anorectal and genital malformation and renal malformations, with usually normal intellect [3, 11]. It results from loss of function of CCNQ, the gene for cyclin M, the activating subunit of CDK10; deficiency of the complex increases ETS2 and alters ciliogenesis, and skewed X inactivation and the absence of affected males suggest male lethality [9, 30, 31]. About half of the alterations described are deletions, so the diagnosis requires methods that detect copy-number variations, and deletions extending to neighbouring genes may give rise to extended and, in one case, lethal forms [3, 4, 9]. The diagnosis should be considered in all girls with anorectal malformation and toe syndactyly, after Townes-Brocks syndrome, the VACTERL association and Feingold syndrome have been distinguished [40, 45, 49]. Treatment is that of the malformations, according to the European guidelines for anorectal malformations and vesicoureteral reflux, with follow-up of renal function, the spine, vision and hearing and an organised transition to adult care [18–20, 50]. Counselling must take into account the de novo origin of most cases, maternal mosaicism and the 50% risk of transmission for carriers, in a context of unpredictable severity [5, 10]. Al Kaissi syndrome, autosomal recessive, results from loss of the other subunit of the complex, CDK10, and combines severe short stature, cervical spine anomalies, facial dysmorphism and moderate to severe intellectual disability; diagnosis requires copy-number and splicing analysis, and management is supportive [6, 28].

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