Grange Syndrome (YY1AP1)

Early-onset multifocal stenotic-occlusive arteriopathy, resembling fibromuscular dysplasia, with brachysyndactyly, bone fragility, congenital heart disease and neurodevelopmental changes of variable penetrance, caused by biallelic loss-of-function variants in YY1AP1.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and clinical delineation

Grange syndrome was described in 1998 by D. K. Grange, I. C. Balfour, S. C. Chen and E. G. Wood, of the Department of Pediatrics of Saint Louis University (Missouri, USA), in a sibship in which four of nine siblings had renal artery stenosis with chronic hypertension, variable stenosis or occlusion of cerebral, abdominal and probably coronary arteries, attributed to fibromuscular dysplasia (FMD), congenital heart anomalies, brachydactyly and syndactyly of the hands and feet and bone fragility consistent with a mild form of osteogenesis imperfecta; three of those affected had mild to moderate learning difficulties, and the parents and the other five siblings had normal hands and feet and no history of excessive fractures [20]. The OMIM catalogue entry, created in April 1998, describes the 29-year-old female proband with a patent ductus arteriosus (PDA) ligated at 14 months, bicuspid aortic valve with mild to moderate regurgitation, residual perimembranous ventricular septal defect, multiple fractures with reduced mineralisation, cerebral occlusions documented at 26 years and complete occlusion of the coeliac trunk with 75% stenosis of the superior mesenteric artery; her 27-year-old brother had a bicuspid valve, mild pulmonary stenosis, bilateral renal stenosis with hypertension and a severe moyamoya cerebral angiographic pattern; a sister, with numerous fractures and hypertension from 5 years of age, died suddenly at 18 years [1].

Because each isolated component of the syndrome (FMD, brachydactyly, syndactyly, osteogenesis imperfecta) was known as an autosomal dominant trait in many families, the 1998 authors considered three explanations for recurrence among siblings of unaffected parents: autosomal recessive inheritance, autosomal dominant inheritance with reduced penetrance, or parental gonadal mosaicism for a mutation in one gene or in contiguous genes [20]. Isolated reports followed that consolidated the phenotype: in 2001, Weymann and colleagues, in Zurich, described a 15-year-old boy with stenoses and occlusions of cranial, renal and coeliac arteries, a basilar artery aneurysm, cutaneous syndactyly and borderline intellectual disability, emphasising that the clinical and radiological pattern differed from FMD and from moyamoya disease [21]; in 2006, Wallerstein and colleagues, in New Jersey, described a 3-year-old girl with brachysyndactyly, renal stenosis with hypertension and bone fragility, without heart disease, which showed that congenital heart disease is not obligatory [22]; and in 2012 Volonghi and colleagues, in Brescia, reported an 18-year-old woman with subarachnoid haemorrhage from rupture of a basilar aneurysm, extensive vasculopathy, facial dysmorphism and brachysyndactyly, proposing the syndrome as an identifiable cause of stroke in young adults [23].

1.2. Identification of the gene and expansion of the spectrum

In 2017, Dianna Milewicz's group in Houston sequenced the exomes of the unaffected parents and two affected children of the original family (designated DVD047) and identified, as the only variants consistent with a recessive model, two nonsense variants in YY1AP1 in compound heterozygosity; Sanger sequencing confirmed them in the third affected sibling [6]. In the same study, homozygous loss-of-function variants were identified in the patients of Weymann and of Wallerstein and in a third child with borderline intellectual disability, and functional studies were performed that placed the protein in the INO80 chromatin remodelling complex and showed its role in the proliferation and differentiation of vascular smooth muscle cells [6]. From then on, the allelic spectrum broadened to intronic variants that alter splicing [10], to a missense allele associated with late vascular onset [11], to intragenic deletions detected by genome sequencing or by copy number variation analysis from exome data [7, 13], and the clinical spectrum extended to haemorrhagic stroke in early childhood [24], to the infant with PDA and hypertension [12], to the first extended family cohort, with eight affected individuals and a predominance of fractures [9], and to diagnosis established solely because of intellectual disability and syndactyly, before any vascular sign [8].

1.3. Nomenclature and definition of the entity

OMIM designates the entity "Grange syndrome; GRNG" and records as alternative titles "arterial occlusive disease, progressive, with hypertension, heart defects, bone fragility, and brachysyndactyly" and "Grange occlusive arterial syndrome"; the phenotype-gene relationship has mapping key 3 (molecular basis known), with autosomal recessive inheritance [1]. Orphanet (ORPHA:79094) defines it as a rare multiple congenital anomaly syndrome characterised by early-onset hypertension and multifocal stenotic lesions of several arteries, including the cerebral, renal, abdominal and coronary arteries, with variable additional features: learning difficulties, mild facial dysmorphism, anomalies of the fingers and toes, bone fragility and congenital heart disease [2]. For the purposes of this article, Grange syndrome is the disease caused by biallelic pathogenic variants in YY1AP1; similar clinical pictures without biallelic YY1AP1 variants — such as the "Grange-like" phenotype described in 2026 with a de novo RNF213 variant [25] — are treated as differential diagnoses. The term "FMD-like" used for the arteriopathy reflects the angiographic classification of the lesion, not identity with adult FMD, whose consensus definition requires the exclusion of monogenic arterial diseases [14, 15].

2. Molecular Genetics and Pathophysiology

2.1. The YY1AP1 gene and its evolutionary origin

YY1AP1 lies at 1q22 and encodes YY1-associated protein 1 (yin yang 1-associated protein 1), identified as a coactivator of the transcription factor YY1 [4, 6]. The gene was cloned in 2001 under the name HCCA2, from hepatocellular carcinomas, in which it was expressed in 79% of samples and not in normal adult liver [3]. The analysis by Kuryshev and colleagues, summarised in OMIM, showed that YY1AP1 arose from fusion of the 5′ region of the ASH1L gene with the 3′ region of the GON4L gene during a tandem segmental duplication on chromosome 1, and that its 3′ end derives from an endogenous retrovirus long terminal repeat (MER51A) inserted into former exon 21 of GON4L; the 750-amino-acid protein shares 748 residues with amino acids 590 to 1337 of GON4L, and expression is ubiquitous, with highest levels in testis and skeletal muscle [3]. This origin has practical consequences: the gene does not exist in the rodent genome, which precludes mouse models and requires the protein to be studied in human cells, and the closest mouse protein (UniProt E9Q507, 2242 residues) shares only about 220 N-terminal amino acids with 80% identity [6, 13, 26]. There are more than nine isoforms; in smooth muscle cells and the aortic wall, the isoforms ENST00000295566 and ENST00000404643 are mainly detected, with a protein of about 88 kDa [6]. The MANE Select transcript is NM_139119.3 (ENST00000355499.9; coding region between nucleotides 268 and 2520), whereas most clinical reports describe the variants on NM_001198903.1, a longer isoform; the difference in numbering between the two transcripts makes it necessary to convert descriptions with a validation tool before comparing reports [5, 8].

2.2. Protein function and cellular mechanism

YY1AP1 is located in the nucleus of smooth muscle cells, in the nucleoplasm and nucleolus, and in the wall of a normal human carotid artery it is found in the nuclei of spindle-shaped smooth muscle cells between the elastic laminae, in the cells of neointimal lesions and in the endothelium of the vasa vasorum [6]. In co-immunoprecipitation assays, YY1AP1 associates with YY1 and with the INO80E and INO80C subunits of the INO80 complex, an ATP-dependent chromatin remodelling complex that takes part in transcriptional regulation, DNA repair and replication [6]. Knockdown of YY1AP1 by RNA interference, in HEK293T cells and in immortalised aortic smooth muscle cells, reduced proliferation, increased the cyclin-dependent kinase inhibitor p21 (WAF1/CDKN1A) and caused cell cycle arrest in G1 and G2 (in G2 in smooth muscle cells), without increased apoptosis [6]. Transforming growth factor β1 (TGF-β1), an inducer of contractile differentiation of smooth muscle cells, increased YY1AP1 levels before increasing smooth muscle α-actin and calponin; blockade of the type I TGF-β receptor prevented this increase, and YY1AP1 deficiency prevented the rise in smooth muscle α-actin and SM22α after exposure to TGF-β1 [6]. In fibroblasts from the proband of the original family, neither full-length nor truncated protein was detected, which is consistent with a loss-of-function mechanism [6]. The p.(Pro360Leu) missense variant (NM_001198903.1 numbering) reduces protein stability in the patient's dermal fibroblasts, in a research assay that is not a clinical test [4, 11].

2.3. From smooth muscle cell to arterial lesion

The resulting phenotype is that of a disease of the vascular smooth muscle cell, neither inflammatory nor atherosclerotic [4]. Guo and colleagues proposed that the combination of dedifferentiation and cell cycle arrest might predispose YY1AP1-deficient cells to proliferate excessively in response to mitogens, or that failure of precursor differentiation might simultaneously generate cells that proliferate aberrantly and cells that differentiate without adequately populating the wall, explaining the coexistence of stenoses and aneurysms in the same patient; this is a hypothesis, supported by analogy with other occlusive diseases due to smooth muscle hyperplasia, such as those associated with ACTA2 and NF1 [6]. The same authors noted that loss of other INO80 complex subunits also reduces proliferation with increased p21 and cited two siblings with aortic hypoplasia, calcified occlusive arterial lesions and hypertension associated with a homozygous INO80D missense variant, which suggests that alterations of this complex may underlie other arteriopathies (indirect attribution by the authors) [6]. There are no pathology specimens that allow histological classification of the lesion in Grange syndrome; in the Uruguayan child who underwent indirect cerebral revascularisation, histology of the arterial wall showed no significant changes [6, 13]. The mechanism of the non-vascular features — brachysyndactyly, bone fragility, heart disease and neurodevelopmental changes — has not been clarified by functional studies [12]; YY1 was one of the first intellectual disability candidate genes identified by trio exome sequencing, and YY1AP1 has detectable expression in the brain, which makes a direct contribution to the cognitive phenotype plausible but not demonstrated [6, 8].

2.4. Inheritance and the role of heterozygotes

Transmission in the original family is consistent with autosomal recessive inheritance, and all patients with molecular confirmation have biallelic variants (homozygosity or compound heterozygosity), with clinically unaffected heterozygous parents [1, 6, 7, 10, 24]. The "autosomal dominant" annotation that the Orphadata inheritance file still shows corresponds to the uncertainty before the gene was found, when the authors considered dominant inheritance with reduced penetrance or gonadal mosaicism [4, 20, 23]. Whether heterozygosity for loss-of-function variants confers an increased risk of arterial disease remains open: the heterozygous mother in the original family had, at 67 years, difficult-to-control hypertension, chronic kidney disease and proximal stenosis of the left renal artery; in a cohort of 282 patients with FMD and 286 matched controls there was no excess of YY1AP1 variants, but a single heterozygous frameshift variant was found in a woman with severe renal and carotid FMD and none in controls [6]; in Rath's family, a heterozygous sister had a 50% stenosis of the external carotid on a single Doppler ultrasound at 9 years, not confirmed on subsequent examinations, and the parents (48 and 50 years) had no lesions [10]; in the French family, the heterozygous father had a hypertensive "mini-stroke" at 30 years without renal stenosis and with concentric left ventricular hypertrophy [7]. These data do not allow penetrance to be estimated or causality to be demonstrated, and the hypothesis of a low-penetrance predisposing allele remains just that [3, 6].

2.5. Variant spectrum and normalisation

The published spectrum is dominated by nonsense and frameshift variants distributed along the gene, with enrichment in the central and C-terminal regions, complemented by two splicing variants, one missense allele and two intragenic deletions [8, 12]. Table 2.1 brings together the published variants converted by VariantValidator (GRCh38) to the MANE transcript and the corresponding ClinVar entry; no conversion was done by hand [5, 27].

Table 2.1. YY1AP1 variants published in Grange syndrome and normalisation to the MANE transcript

Three nomenclature notes avoid errors of interpretation. For the Brazilian variant, the published protein description does not match the reference sequence according to VariantValidator (residue 390 of NP_001185832.1 is a phenylalanine), and the paper provides no genomic coordinates that would allow the two descriptions to be reconciled; the published description is recorded alongside the normalised prediction [5, 24]. In the Unsel-Bolat report, the inherited variant c.1489_1492del, described on NM_139119.3, appears in the abstract with the protein designation of the long isoform (p.Glu636ProfsTer13) and in the discussion with that of the MANE isoform (p.Glu498ProfsTer13); both designations refer to the same genomic allele, which is the homozygous allele of the Wallerstein patient [5, 8]. The homozygous variant c.895C>G p.(Leu299Val) (NM_001198903.1) found in the exome of the French proband was classified by the authors as likely benign and non-causal; the cause was the deletion of exons 7 and 8 [7]. ClinVar contains other YY1AP1 loss-of-function variants classified as pathogenic or likely pathogenic without a verified published phenotypic description (for example c.583+1G>A, c.207del, c.743del, c.-21+1G>T and the deletion NM_001198903.1:c.998_1293del, the designation of ClinVar record 1172641, which spans at least one intron and therefore does not define the genomic breakpoints), variants of uncertain significance (VUS) such as c.923G>C p.(Cys308Ser), c.403A>G p.(Ile135Val), c.567A>T p.(Lys189Asn) and c.1303del, and numerous large copy number variations at 1q21–q23 that span the gene and whose classification refers to the CNV as a whole, not to Grange syndrome [27].

2.6. Genotype-phenotype correlations, penetrance and expressivity

There is no established genotype-phenotype correlation: variability is marked between families and within the same family, and patients with biallelic frameshift variants do not share the same picture [10, 12]. The only suggestive exception is the p.(Pro360Leu) missense allele, associated with late vascular onset — hypertension at 25 years, ischaemic stroke at 42 and diagnosis at 51 — and with absence of developmental delay and bone fragility, in a single individual [8, 11]. Unsel-Bolat and colleagues speculated that distal truncations in exon 11 (MANE numbering), which preserve parts of the N-terminal and central domains, might be associated with later or attenuated vascular manifestations and a predominantly neurodevelopmental phenotype; the authors themselves classify the hypothesis as speculative [8]. Renal and carotid arteriopathy behaves as the component with the highest penetrance, but with a very variable age at onset, which suggests age-dependent penetrance; brachysyndactyly, bone fragility, congenital heart disease and learning difficulties are the most variable components [8, 10]. In Rath's family, none of the three siblings had developmental delay and only two had syndactyly; in Akalin's Turkish family, bone fragility was the most frequent presenting manifestation [9, 10].

2.7. Allelic disorders, modifiers and dual diagnoses

No allelic disorders of YY1AP1 with a phenotype distinct from Grange syndrome are known in the sources consulted. Somatic amplification of YY1AP1 acts as an oncogenic factor in EpCAM+ AFP+ hepatocellular carcinoma, a context unrelated to the germline disease [3, 6]. In one patient from the Turkish cohort, a 4-month-old girl, a second pathogenic biallelic variant coexisted in CLMP (NM_024769.5 c.167dup p.(Asn56LysfsTer2)), the gene for autosomal recessive congenital short bowel syndrome (OMIM 615237), which constitutes a dual molecular diagnosis, a phenomenon to be expected in consanguineous families [9, 28]. In the Uruguayan child, the dyslipidaemia (LDL cholesterol 205 mg/dl at 6 years) was attributed to polygenic hypercholesterolaemia on the basis of a polygenic score, not to Grange syndrome [13].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and what they measure

All clinical knowledge of Grange syndrome comes from case reports and small family series: the original American family (4 affected), three isolated patients described before identification of the gene (Switzerland, USA and Italy), a German family with three siblings, a Canadian woman with a missense allele, a Brazilian girl, a Uruguayan girl, a Turkish infant girl, an extended consanguineous French family with four affected, three siblings cited by Unsel-Bolat (Alsadiqi), a Turkish adolescent girl and, in 2026, a consanguineous Turkish family with eight affected [7–10, 12]. Three aggregate tables summarise these observations with different denominators (Table 3.1). The percentages describe the frequency of each finding among published patients in whom the finding was assessed; they are not estimates of population penetrance, are subject to publication bias (cases with severe vascular disease are more easily diagnosed and published) and mix very different ages, from infants to adults aged 53 years [7, 8]. Table 2 of Unsel-Bolat contains transcription inconsistencies (for example, the Uruguayan girl appears as a 7-year-old boy and the row for one patient from the original family reproduces data from the Wallerstein patient), so its aggregate counts should be read with that limitation [8, 13, 22].

Table 3.1. Frequency of findings in aggregate literature reviews (denominator = patients in whom the finding was assessed)

3.2. Arterial disease: renal territory and hypertension

Hypertension is the most constant finding among patients old enough to manifest it, and results mainly from unilateral or bilateral renal artery stenosis, sometimes with involvement of the intraparenchymal branches (renal vascular "pruning" in the original proband) [10, 12]. Age at onset ranges from infancy to adulthood: hypertension at 4 months and renal stenosis at 15 months in the Wallerstein patient, with angioplasty at 28 months and repeated at 7 years; hypertension at 3 years, with a previous thalamocaudate haemorrhage at 15 months and bilateral renal stenosis documented at 5 years, in the Brazilian girl; bilateral renal stenosis at 6 years, a non-functioning left kidney and progressive renal failure at 13 years in the 29-year-old French man; and renal stenosis only at 52 years in the woman with the missense allele [6–8, 24]. In Saida's review, 10 of 11 patients with renal stenosis had early uncontrolled hypertension, all needed several antihypertensive drugs and 4 of 12 (33.3%) had undergone renal angioplasty [24]. A small kidney is an indirect sign: in the Brazilian girl, the left kidney measured 7.2 × 3.2 cm (−2.2 SD) at 7 years [24]. Left ventricular hypertrophy, described in several patients, may be secondary to hypertension [8, 24].

3.3. Arterial disease: carotids, intracranial circulation and stroke

Bilateral internal carotid artery (ICA) stenosis is, with hypertension and renal arteriopathy, the core of the phenotype, and was usually diagnosed in the second decade (at 13 and 15 years in the three German siblings; at 10, 15, 18 and 26 years in other patients) [10]. The disease progresses to occlusion with a collateral network: in the eldest sister of the German family, angiography showed occlusion of the left ICA just after the bifurcation and severe stenosis on the right, with collaterals from the thickened ascending pharyngeal artery, the meningohypophyseal trunk, the inferolateral trunk and branches of the middle meningeal and internal maxillary arteries [10]. Collateralisation at the skull base resembles that of moyamoya disease — the brother of the original proband had a severe moyamoya pattern and the Canadian woman extensive "moyamoya-like" collateralisation — but the Uruguayan child had severe stenoses of both vertebral arteries and the right ICA and a short occlusion of the left ICA without moyamoya phenomenon [1, 11, 13]. Basilar artery aneurysms (with rupture and subarachnoid haemorrhage at 15 and 18 years), multiple intracranial aneurysms and tortuosity of the cerebral arteries have been described [12, 21, 23]. Periventricular hyperintense lesions suggestive of small vessel disease were described in the brother of the original proband and in the Wallerstein patient at 15 years [6].

Cerebrovascular events include TIA, arterial and watershed ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage, and occur from early childhood. The Uruguayan girl had two TIAs at 6 years and an ischaemic stroke at 7 [13]; the Brazilian girl had, at 15 months, seizures, right hemiparesis and a left thalamocaudate haemorrhage without cerebral vascular anomaly on MR angiography, attributed by the authors to severe hypertension [24]; the Turkish infant girl had, at 15 months, a left occipitoparietal subdural haematoma with sudden loss of movement of the right lower limb [12]; the French boy had, at 16 months, a subacute ischaemic stroke in the left anterior territory and the watershed zones, with occlusion of the left cervical ICA and hemispheric atrophy [7]. In the French paper, the abstract classifies this stroke as haemorrhagic, but the results and imaging describe an ischaemic stroke; the description in the results prevails [7]. Presenting neurological symptoms in adolescents may be non-specific: headaches, dysarthria, transient impairment of fine motor skills and choreic movements at 15 years in the eldest German sister [10]. In Saida's review, 10 of 11 patients had cerebral artery stenosis and 6 of 11 (54.5%) had had a stroke [24].

3.4. Arterial disease: visceral, coronary, aortic and peripheral territories

Stenoses of the coeliac trunk and superior mesenteric artery are frequent and may cause abdominal angina and intestinal ischaemia: the original proband had occlusion of the coeliac trunk and superior mesenteric artery complicated by intestinal ischaemia requiring surgery, and the Swiss boy had recurrent abdominal pain [6, 21]. Stenoses of the common hepatic, splenic and external iliac arteries and a renal aneurysm have been described [6, 11, 12]. Coronary disease appeared at 32 years in the original proband (branches of the left anterior descending artery) and with chest pain and coronary narrowing at 13 years in another affected member of the sibship; a sister died suddenly at 18 years, and in the French family one brother with a compatible picture died at 15 years and another at 2 years of unknown cause [1, 6–8]. The aorta may be involved: a 4.9 cm ascending aortic aneurysm with bicuspid valve in the brother of the original proband and mild dilatation of the aortic isthmus in the Italian patient [6, 12]. Recurrent Raynaud phenomenon, up to three times a week, led to hospitalisations and treatment with intravenous alprostadil in one of the German sisters [10].

3.5. Heart

The congenital heart anomalies described are PDA (original family and Turkish infant), bicuspid aortic valve, sometimes stenotic, perimembranous ventricular septal defect and mild pulmonary stenosis [1, 12]. The French series showed that cardiac involvement is more diverse: concentric left hypertrophic cardiomyopathy with a septum of up to 12 mm in a 9-year-old girl, left ventricular hypertrophy in an infant girl and left ventricular dilatation with systolic dysfunction in the 29-year-old man [7]. Mitral valve prolapse was described in the Turkish adolescent and long QT syndrome with an implantable cardioverter-defibrillator in the original proband [6, 8].

3.6. Skeleton and limbs

Brachydactyly (of all digits or mainly the 2nd and 5th), clinodactyly of the 5th finger and cutaneous syndactyly, most often between the 3rd, 4th and 5th fingers and between the 2nd and 3rd toes, are the most constant extravascular signs and, being visible at birth, the most useful for early suspicion [7, 12]. Bony syndactyly may be present (distal phalanges of the 3rd and 4th fingers in the French boy) [7]. Hand radiography shows phalangeal shortening, for example of the middle phalanx of the 5th finger, with appropriate bone age [24]. Mild thoracolumbar scoliosis and pectus excavatum have been described [24].

Bone fragility, resembling mild osteogenesis imperfecta, was the feature that prompted the initial comparison with osteogenesis imperfecta, but up to 2023 it had been described in only two families and occurred in about 30% of tabulated patients [7, 10, 20]. The 2026 Turkish cohort changed this perspective: in eight affected members of a consanguineous family, multiple fractures were the most common presenting manifestation (6/8), with a mean age at first fracture of 3.6 ± 1.7 years and a mean baseline bone mineral density (BMD) Z-score of −4.1 ± 1.6 [9]. Data available only in abstract form do not show whether this frequency reflects an effect of the familial allele, of consanguinity or of the assessment method [9].

3.7. Neurodevelopment, growth and other systems

Mild to moderate learning difficulties, borderline or mild intellectual disability and speech articulation disorders occur in about half of patients; some have normal or above-average cognitive performance, such as the eldest German sister, a university student [10, 12]. Saida and colleagues allow that part of the cognitive deficit may be secondary to silent strokes [24], but the mild intellectual disability of the Turkish adolescent, without any detected vascular lesion, and that of the 9-year-old French girl without stroke indicate that the neurodevelopmental component may be primary [7, 8]. MRI of the Turkish adolescent showed a mega cisterna magna [8].

Intrauterine growth restriction (IUGR) occurs in about half of the cases assessed, sometimes severe and early (22–27 weeks in the French boy, before 22 weeks in his sister), associated with high resistance in the uterine arteries, which led the French authors to suggest a contribution from heterozygous maternal vascular disease [7]. Other findings described are mild facial dysmorphism (hypertelorism, frontal bossing, epicanthic folds, low nasal root, saddle nose, low-set ears, high-arched palate), livedo reticularis, keratosis pilaris, strabismus, hypothyroidism (subclinical at 6 years in the Uruguayan child; at 38 years in the Canadian woman), advanced puberty with obesity in a French girl and accessory breast tissue in the Turkish adolescent [6–8, 12, 13, 24].

3.8. Natural history and chronology

Table 3.2. Chronology of the manifestations described by age (documented examples)

Arterial disease is dynamic and potentially progressive, with no uniform timetable, and lesions absent on one examination may appear years later: the Wallerstein patient had renal stenosis at 15 months and carotid stenoses with collaterals at 15 years; girl DVD112 described by Guo had no stenoses on CT angiography at the age at which she was assessed [6, 8]. There are no data on treated versus untreated disease that would allow outcomes to be compared; the reports describe patients who received several antihypertensive drugs and, in some cases, angioplasty or cerebral revascularisation, with variable outcomes and short follow-up [13, 24].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Suspicion rests on the association of a non-atherosclerotic, non-inflammatory stenotic-occlusive arteriopathy, with onset in childhood or young adulthood, with digital anomalies. Hausman-Kedem and colleagues include brachydactyly and syndactyly as a specific clinical clue to Grange syndrome in the assessment of children with cerebrovascular disease, alongside the dysmorphism of Down, Williams and Alagille syndromes, the café-au-lait macules of neurofibromatosis type 1 and the segmental haemangiomas of PHACES syndrome [14]. Saida and colleagues recommend considering the syndrome in the presence of childhood-onset hypertension and/or haemorrhagic stroke, and stroke associated with renal stenosis [24]; Volonghi and colleagues, in the presence of stroke in a young adult with extensive vasculopathy and brachysyndactyly [23]. From 2026 a third scenario is added: intellectual disability or developmental delay with corrected syndactyly, even without any vascular sign, as in the Turkish adolescent diagnosed through the child psychiatry clinic, in whom renal, carotid, vertebral and peripheral Doppler ultrasound was normal [8]. In Akalin's family, multiple fractures in childhood were the most frequent presentation, which places the syndrome in the differential diagnosis of bone fragility with brachysyndactyly [9].

Table 4.1. Scenarios of suspicion by age

4.2. Warning and emergency signs

In patients with an established diagnosis, chest or abdominal pain should be treated as an emergency, as it may indicate coronary or mesenteric ischaemia [7, 24]. Signs of TIA, stroke and arterial dissection — focal neurological deficit, unilateral neck pain or headache, partial Horner syndrome, amaurosis fugax — require immediate assessment; the international FMD consensus recommends teaching these signs to patients [15]. An unexplained rise in blood pressure or a decline in renal function after renal angioplasty calls for imaging reassessment before the scheduled time [15]. In a child with cerebral vasculopathy, episodes of hypotension or hypoxia are situations at risk of infarction, because of impaired cerebral autoregulation [14]. Seizures may occur with or without cerebral stenosis and may be the first manifestation of severe hypertension in an infant [24].

Among the general signs of renal and cerebrovascular FMD in the international consensus — hypertension before 30 years of age, accelerated, malignant or grade 3 hypertension (>180/110 mmHg), hypertension resistant to three drugs including a diuretic, a unilateral small kidney without a urological cause, an abdominal bruit without atherosclerosis, suspected renal dissection or infarction, severe or chronic migraine, pulsatile tinnitus, a cervical bruit, stroke, TIA or amaurosis fugax and unilateral neck pain with focal signs — the age criteria and those for dissection were established in adults and apply to Grange syndrome only by analogy [15].

4.3. Newborn screening

There is no newborn screening for Grange syndrome, and no biochemical biomarker that would allow it [4].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal clinical criteria or scoring system for Grange syndrome. Diagnosis is confirmed by identification of biallelic pathogenic or likely pathogenic YY1AP1 variants (homozygosity, or compound heterozygosity with confirmation that the variants are in trans), in a patient with a compatible phenotype [4, 6]. Arterial imaging, densitometry and radiographs demonstrate components of the phenotype, but none of these assessments is specific or allows the syndrome to be distinguished from other causes of FMD or of paediatric arteriopathy [4]. The international consensus definition of FMD requires the exclusion of monogenic arterial diseases; the term "FMD" therefore applies to the angiographic lesion (focal or multifocal) and does not replace the syndromic diagnosis [15]. The reports describe focal lesions and multifocal "string-of-beads" lesions in the same patient, with a predominance of the focal appearance, which is also the usual pattern in children [6, 14].

5.2. Genetic testing: strategy and limitations

Given the heterogeneity of childhood cerebral and systemic arteriopathies, the 2024 review recommends genetic testing in all children with complex vascular disease, after clinical and radiological phenotyping, preferably by trio exome or genome sequencing, with periodic reanalysis of negative results [14]. In the particular case of YY1AP1, each type of published variant highlights a different technical limitation. Deep intronic variants that create cryptic splice sites escape analyses restricted to exons: the c.997+23T>G variant (NM_001198903.1) was only found when exome analysis included the regions within ±50 base pairs of the exons, an analysis limited to exons and canonical sites (±5 bp) would have missed the diagnosis, and confirmation required RNA study by RT-PCR [10]. Small intragenic deletions fall below the detection threshold of chromosomal microarray: the homozygous 1.84 kb deletion of exons 7 and 8 was not detected by array-CGH or by a limb malformation panel (which did not include YY1AP1) and was only identified by CNV analysis from exome read depth (XHMM), with confirmation by PCR [7]. Deletions in compound heterozygosity with a point variant may go unnoticed when only the point variant is sought: the paternal deletion of about 6.8 kb including the first coding exon was detected on genome sequencing by inspection of coverage and by a structural variant algorithm, and the authors emphasise that it could have escaped the exome [13]. Restricted clinical exome panels, such as the one of about 4900 genes used by Unsel-Bolat, do not cover all genes or non-coding regions [8].

Rath and colleagues recommend that YY1AP1 analysis should cover all coding transcripts, the regions close to splice sites and copy number variation, recalling the 23 YY1AP1 CNVs recorded in ExAC [10]. GeneGuidance concludes that exon-level copy number analysis is needed before YY1AP1 is considered excluded [4]. A negative YY1AP1 result does not exclude a similar phenotype of another genetic cause: the adolescent girl from Izmir with a "Grange-like" phenotype had a negative exome and a de novo RNF213 variant on trio genome sequencing [25].

5.3. Interpretation and report content

The report should state the gene, the reference transcript with version — ideally the MANE Select NM_139119.3, with the correspondence to the NM_001198903.1 used in the literature —, the HGVS description at DNA level and of the predicted protein, the zygosity, the classification according to ACMG/AMP criteria and, in compound heterozygosity, demonstration that the variants are in trans by parental testing [5, 13]. The published loss-of-function variants were classified with the criteria PVS1 (null variant in a gene in which loss of function is a mechanism of disease), PM2 (absence or rarity in population databases) and PM3 (in trans with a pathogenic variant in a recessive disease) [12, 13]. For intronic variants, classification as pathogenic required evidence of an effect on RNA [10]; for the only missense allele, functional support came from a protein stability assay in fibroblasts, which is not available in the clinical setting [4, 11]. A VUS in YY1AP1 in a patient with a suggestive phenotype justifies segregation studies, a search for a second variant (including CNVs and intronic regions) and, if possible, RNA study [7, 10]. The proportion of variants detectable by each technique is not equivalent to the clinical sensitivity of the test, which has not been measured in any series.

5.4. Phenotypic assessment at diagnosis

Assessment at diagnosis, by analogy with the FMD consensus and with the review of paediatric arteriopathies, includes imaging of all vessels from brain to pelvis at least once by contrast-enhanced CT angiography or MR angiography; CT angiography is the preferred modality for renal FMD in adults because of its greater spatial resolution, and MR angiography is the alternative when CT is contraindicated [15]. In children, MR angiography and CT angiography detect stenosis of the main renal artery trunk, but branch stenoses, which are more frequent, are better diagnosed by renal digital subtraction angiography; cerebral catheter angiography is usual in moyamoya and stenotic-occlusive arteriopathies, and concomitant systemic angiography should be considered [14]. Persu and colleagues point out that formal exclusion of renal stenosis can only be achieved by catheter angiography [29]. Catheter angiography is indicated when the result changes management, with measurement of the translesional pressure gradient (Pd/Pa) before deciding on angioplasty [15]. Carotid and renal Doppler ultrasound is useful for follow-up, but does not assess the distal ICA, the vertebral arteries or the intracranial arteries [15]. The baseline assessment also includes blood pressure measurement (with 24-hour ambulatory monitoring if needed), echocardiography, DXA densitometry, radiographs of the hands and skeleton and developmental assessment [4, 14]. In the Uruguayan child, investigation for secondary hypertension (catecholamines, cortisol, ACTH, renin, aldosterone, vanillylmandelic acid) and DMSA renal scintigraphy were normal, despite the later bilateral renal stenosis, which shows that biochemical investigation does not exclude the arteriopathy [13].

5.5. Practical algorithm

Table 5.1. Diagnostic sequence proposed from the sources

5.6. Prenatal and preimplantation diagnosis

IUGR, frequent in affected fetuses, is not specific. When both familial variants are known, molecular prenatal diagnosis is possible: in the French family, identification of the deletion allowed the parents of the affected boy to request prenatal diagnosis in the next pregnancy, which confirmed an affected daughter [7]. Preimplantation genetic testing applies according to the general principles for monogenic diseases with known familial variants; the sources consulted do not describe its use in Grange syndrome.

6. Differential Diagnosis

6.1. Comparative table

Table 6.1. Differential diagnosis of Grange syndrome

6.2. Fibromuscular dysplasia and paediatric arteriopathies

The most frequent differential diagnosis is FMD itself, but the comparison should be made with paediatric FMD and not with adult FMD. Adult FMD affects mainly women (80–90%), is multifocal in about 85% of cases, has a mean age at diagnosis of 45 to 55 years, is rare in children in its multifocal form and has familial occurrence in 1.9–7.3% of patients in modern registries [15, 26]. In children, focal lesions predominate, the histology is mainly intimal fibroplasia, common to other monogenic arteriopathies of childhood, and the "string-of-beads" appearance is not very specific; Hausman-Kedem and colleagues argue that paediatric FMD is a heterogeneous group of monogenic arteriopathies not yet defined and propose the term "cerebral and systemic arteriopathies of childhood" (CSA-c) to describe simultaneous cerebral and extracranial involvement [14]. In the US FMD registry, 33 paediatric patients had renal involvement in 97%, a mean age at diagnosis of 8.4 years and 62% were female, and Singh and colleagues propose designating focal renal stenosis in children as "aorto-renal dysplasia", listing YY1AP1 among the genes associated with isolated renal artery stenosis, alongside NF1, JAG1, NOTCH2, ELN, TSC1, TSC2, PDGFRB and NOTCH3 [43]. In Grange syndrome, the vasculopathy is angiographically more consistent with focal FMD, but there are "beaded" segments in some patients, and the female predominance in the series (about 70%) has no established explanation [6, 7]. The absence of digital anomalies, bone fragility and heart disease does not exclude the syndrome, because they are components of variable penetrance [10].

6.3. Syndromes with focal renal stenosis and middle aorta involvement

Neurofibromatosis type 1, Williams-Beuren syndrome and Alagille syndrome are the most frequent syndromes with focal renal stenosis in children, and the angiographic appearance is indistinguishable from that of paediatric focal FMD, often with coarctation of the abdominal aorta (middle aortic syndrome) [29]. In NF1, hypertension occurs in 16–19% of children, renal stenosis is the most frequent cause, and the vasculopathy may progress rapidly [29]; the cutaneous and ophthalmological criteria and the absence of brachysyndactyly guide the diagnosis. In Williams-Beuren syndrome, supravalvular aortic stenosis is the most common anomaly, and the face, behaviour and hypercalcaemia guide the diagnosis [29, 32]. In Alagille syndrome, cholestasis, peripheral pulmonary artery stenosis, butterfly vertebrae and the typical face distinguish the entity; renal stenosis is rare (1 in 268 and 2 in 187 patients assessed in two series), but moyamoya may be present in up to a third [29, 35].

6.4. Moyamoya and phenocopies

Moyamoya disease and moyamoya syndrome share with Grange syndrome terminal ICA stenosis with collaterals, and up to 15% of patients with moyamoya have extracranial or systemic involvement, including hypertension [14]. RNF213 variants are associated with moyamoya with early-onset systemic involvement that may be confused with paediatric FMD [14]. In 2026, a 15-year-old girl with moyamoya revascularised at 1.5 and 3 years, bilateral renal stenosis, brachydactyly, toe syndactyly, a broad left thumb, intellectual disability and facial dysmorphism had a negative exome and a de novo likely pathogenic RNF213 variant (c.12341C>G) on trio genome sequencing — the first published "Grange-like" phenotype of another genetic cause [25]. In ACTA2 Arg179 syndrome, brain imaging shows dilatation of the ICA up to its terminal portion, distal occlusion, a straight course of the intracranial arteries and absence of moyamoya collaterals, with congenital mydriasis in all patients and fully penetrant aortic disease by 25 years [37]; the syndrome belongs to the group of hereditary aortopathies. Moyamoya disease and monogenic moyamoya angiopathy enter the differential diagnosis.

6.5. Bone fragility and digital anomalies

The bone fragility of Grange syndrome was initially compared to mild osteogenesis imperfecta [20]. The association of fractures with brachysyndactyly and with hypertension or arterial stenosis is the element that argues against classic osteogenesis imperfecta, and vascular disease may only appear years later, as in Akalin's patients who presented with fractures [9]. Isolated and syndromic syndactylies have their own genetic differential diagnosis; in patients with syndactyly and hypertension, developmental delay or fractures, YY1AP1 should be included in panels or exome analysis, because a limb malformation panel without YY1AP1 delayed the diagnosis in the French boy [7, 8].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no disease-modifying therapy and no specific guideline; management is based on surveillance and treatment of complications by a multidisciplinary team (genetics, nephrology and hypertension, neurology and interventional neuroradiology, vascular surgery, cardiology, orthopaedics and bone endocrinology, hand surgery, development) [4, 14]. The reference for the arteriopathy is the First International Consensus on the diagnosis and management of FMD, commissioned by the "Hypertension and the Kidney" working group of the European Society of Hypertension (ESH) and by the Society for Vascular Medicine (SVM), which harmonises the 2014 European and American positions; the document focuses on adults, does not mention Grange syndrome and rests mainly on expert opinion, so its application here is by analogy with the vascular phenotype [4, 15]. For children, the 2024 review on cerebral and systemic arteriopathies of childhood notes the absence of evidence-based guidelines [14]. Viora-Dupont and colleagues propose, for Grange syndrome, the same follow-up recommended in FMD — periodic Doppler ultrasound examinations, careful assessment of chest or abdominal pain and signs of ischaemia —, detection and treatment of hypertension, prevention of vascular risk factors and antiplatelet therapy if stroke or TIA occurs [7].

7.2. Hypertension and renovascular disease

Because the ideal blood pressure target in FMD is unknown, the international consensus recommends following general hypertension guidelines (ACC/AHA 2017 and ESC/ESH 2018 at the time of the document) and states that angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) have been recommended in renovascular hypertension; blood pressure control is especially important when aneurysms are present [15]. In a child with cerebral vasculopathy, lowering blood pressure must balance renal protection against maintenance of cerebral perfusion, because the combination of cerebral occlusive disease with vascular smooth muscle dysfunction impairs autoregulation and episodes of hypotension or hypoxia may precipitate infarcts [14]. In NF1 and the other paediatric causes of renal stenosis, medical treatment is often the first step, to allow maximal growth before any intervention, although it is often insufficient [29].

There is a practical divergence regarding ACE inhibitors. Karakaya and colleagues replaced the ACE inhibitor with a calcium channel blocker in the Turkish infant after diagnosis, because of the risk of acute kidney injury with ACE inhibitors should bilateral renal stenosis develop [12]; in the Uruguayan child, enalapril was replaced by propranolol when bilateral renal stenosis of more than 50% was documented [13]. The FMD consensus, for its part, mentions ACE inhibitors and ARBs as recommended in renovascular hypertension [15]. The sources consulted do not resolve this divergence for Grange syndrome. In the reports, patients needed several drugs: ramipril, metoprolol and rilmenidine in a German patient; olmesartan medoxomil and amlodipine in her sister; ramipril monotherapy in the brother [10]; amlodipine and then carvedilol in the Brazilian girl [24]. These regimens describe cases, not recommendations.

7.3. Renal revascularisation

The international consensus proposes a protocol for angiography and percutaneous transluminal angioplasty (PTA) in renal FMD, with an aortogram if there is no prior imaging, selective renal arteriography in multiple projections, simultaneous measurement of the translesional gradient with a pressure wire and a decision on angioplasty using a gradient threshold of 10% of mean aortic pressure (Pd/Pa <0.90), extrapolated from atherosclerotic stenosis and not validated in FMD [15]. The initial balloon is chosen according to the diameter of the normal distal artery and increased in 0.5 mm increments until the gradient disappears or falls below 10%; the procedure is stopped if there is pain during inflation or a complication; stenting is not indicated in FMD and is reserved for complications (flow-limiting dissection, pseudoaneurysm, rupture), some cases of primary dissection or treatment of aneurysm [15]. Surgery is reserved for complex bifurcation or branch lesions, stenoses associated with complex aneurysms or failure of angioplasty, and repeated angioplasties should be undertaken with caution so as not to compromise surgical options [15]. In a meta-analysis of 11 studies cited in the consensus, cure of hypertension (<140/90 mmHg without drugs) after PTA in FMD was only 36% (14–85%), more likely in young patients and with hypertension of short duration, and 18% needed a further procedure; focal FMD had a higher cure rate than multifocal FMD [15].

In children, PTA is usually reserved for symptomatic stenosis despite optimised medical therapy, aneurysm rupture or dissection, because of periprocedural morbidity; blood pressure may fall abruptly after renal angioplasty, requiring monitoring and withholding of antihypertensive drugs during the procedure [14]. In syndromic focal renal stenoses, the preferred revascularisation is renal PTA, combined with aortic angioplasty or stenting if there is abdominal coarctation, and renal stenting or cutting balloons in children are controversial and restricted to specialised centres [29]. In NF1, PTA had technical success of 67–72% and surgery of 78–90%, with resolution of hypertension in up to 71% and 97%, respectively, and restenosis after PTA in up to 44% [29]. In Grange syndrome, renal angioplasty was performed in about a third of the patients reviewed up to 2019 [24], including the Wallerstein patient at 28 months and again at 7 years [6, 8] and the Uruguayan child at 10 years, with incomplete dilatation and restenosis at 11 years [13].

7.4. Antiplatelet therapy, stroke and dissection

In the absence of contraindication, the international consensus considers antiplatelet therapy with aspirin (acetylsalicylic acid) 75–100 mg daily reasonable in patients with FMD, whether symptomatic or not, to prevent thrombotic and thromboembolic complications, acknowledging that there are no controlled trials or data favouring one drug; the benefit should be weighed against the bleeding risk, including previous subarachnoid haemorrhage or a large intracranial aneurysm [15]. This weighing carries particular weight in Grange syndrome, in which intracerebral haemorrhage, subdural haematoma and ruptures of basilar aneurysms in childhood and adolescence have been described [12, 21, 23, 24]. In a child with arterial ischaemic stroke, initial antithrombotic treatment is an antiplatelet agent (aspirin 3–5 mg/kg/day) or an anticoagulant (low-molecular-weight or unfractionated heparin) according to the aetiology, and antiplatelet therapy is the basis of secondary prevention in arteriopathies, with uncertain optimal duration and no data on lifelong use in renal, mesenteric, coronary or peripheral arteriopathies [14]. In cervical dissection associated with stroke or TIA, the consensus applies to FMD the recommendation of an anticoagulant or antiplatelet agent for at least 3–6 months, followed by prolonged antiplatelet therapy, and reserves stenting for persistent ischaemia despite optimised medical therapy [15]. In the Uruguayan child, aspirin and clopidogrel were used after the stroke [13].

7.5. Cerebrovascular disease, cerebral revascularisation and aneurysms

For the moyamoya-type component, the Japanese (2021), European (European Stroke Organisation, ESO, 2023) and American (AHA/ASA, 2021) guidelines, compared by Rifino and colleagues, agree in suggesting antiplatelet therapy in ischaemic moyamoya, with low levels of evidence and Japanese caution about prolonged use; in haemorrhagic moyamoya, direct or combined revascularisation is considered reasonable (Japan, grade B), recommended if there is haemodynamic compromise and choroidal collaterals (ESO, weak recommendation, very low evidence in paediatrics) or with class 2a in adults (AHA/ASA); in ischaemic moyamoya, revascularisation is considered in the presence of symptoms and markers of haemodynamic compromise [44]. These guidelines refer to moyamoya angiopathy and apply to Grange syndrome only by analogy. The Uruguayan child, without moyamoya phenomenon, underwent staged bilateral indirect revascularisation at 7 and 8 years; the report does not describe further cerebrovascular events after revascularisation [13]. Before any cerebral revascularisation, extracranial arterial involvement should be known, because it affects anaesthesia; perioperative blood pressure must avoid both hyperperfusion and haemorrhage and infarction due to hypoperfusion, and may fall after revascularisation [14]. Intracranial aneurysms in FMD are treated as outside it (clipping or embolisation), with imaging surveillance of untreated aneurysms without a defined optimal frequency; rupture of unruptured intracranial aneurysms in the general population is less than 1% per year, and it is unknown whether FMD increases that risk [15].

7.6. Visceral, coronary and aortic disease

Abdominal pain and chest pain require urgent assessment, as they may reflect mesenteric or coronary ischaemia [7, 24]. In renal or visceral dissections in FMD, the consensus describes short-term empirical anticoagulation (3–6 months) or antiplatelet therapy, and intervention only if there is progressive malperfusion, progression of the dissection or a secondary aneurysm [15]. Outside FMD, intervention for renal or visceral aneurysms is usually offered above 2 cm, and many experts consider lower thresholds in women of childbearing age planning pregnancy [15]. Coronary disease in Grange syndrome (stenosis at 32 years, narrowing at 13 years, sudden death at 18) is more frequent than in typical FMD, in which the consensus does not recommend coronary imaging without symptoms [6, 8, 15]; the sources consulted do not define a specific coronary screening strategy for the syndrome. The ascending aortic aneurysm with bicuspid valve observed in the original family justifies echocardiographic assessment of the aorta [6].

7.7. Bone fragility

The only therapeutic observation directed at a component of the syndrome is that of the Turkish cohort: three patients with significant bone fragility received an intravenous bisphosphonate for at least two years, and the mean BMD Z-score went from −4.9 ± 1.9 to −2.4 ± 0.7 [9]. This is an uncontrolled before-and-after comparison in three patients from a single family, read only in abstract form, that does not state the drug, the dose or the effect on fractures; it does not establish an indication [4, 9]. In the absence of a published dose for Grange syndrome, the regimens applicable by analogy are those for paediatric osteoporosis of monogenic cause and for osteogenesis imperfecta. The review by Cannalire and colleagues (2024) indicates bisphosphonates in difficult-to-treat secondary osteoporosis and recurrent fractures, especially in early-onset monogenic forms, considers the intravenous route more beneficial for vertebral fractures and acknowledges that there is no consensus on drug, dose and duration [45]. In the GeneReviews chapter on osteogenesis imperfecta, bisphosphonates increase bone density but the Cochrane review did not demonstrate a reduction in fracture incidence, although a multicentre study of 466 patients associated treatment with higher vertebral density and a lower probability of fracture and scoliosis [42].

Table 7.1. Bisphosphonates in children and adolescents: reference regimens by analogy (off-label use in Grange syndrome) and comparison with the labels

Two aspects of Grange syndrome weigh on the choice. First, renal arteriopathy may reduce renal function, and the zoledronic acid labels contraindicate it with a creatinine clearance below 35 ml/min and require assessment of renal function before each dose, as does the pamidronate label [46–48]. Second, the dose reference is that of the paediatric review and not that of the labels, which have no paediatric indication; treatment should be given in a centre with experience of paediatric bisphosphonates [45]. The most common adverse effects are a flu-like syndrome after the first intravenous infusion, transient hypocalcaemia and, with the oral route, gastrointestinal symptoms; osteonecrosis of the jaw has not been described in children, and dental extractions should not coincide with the period immediately before or after infusions [42]. During treatment, Cannalire and colleagues monitor bone formation markers, parathyroid hormone (PTH) and 25-hydroxyvitamin D every 6 months, with supplementation to values above 30 ng/ml, and DXA every 12 months [45]. The recommended calcium intake is 200 mg/day from 0 to 6 months, 260 mg/day from 6 to 12 months and 700 mg/day above 1 year, and vitamin D supplementation 400 IU/day in the first year of life [45]. The Portuguese SmPC and the Brazilian package insert for these drugs were not consulted, as this is not disease-directed therapy.

7.8. Limbs, development and rehabilitation

Syndactyly is corrected surgically in early childhood (at 1 year in the Uruguayan child, at 4 years in the Turkish adolescent, in early childhood in one of the German sisters) [8, 10, 13]. Developmental assessment and educational support should be offered according to need [4]; the Turkish adolescent was followed in child psychiatry with pharmacological treatment and behavioural recommendations for communication difficulties and social isolation [8]. Rehabilitation after stroke allowed motor and speech recovery in the Brazilian girl and the Turkish infant [12, 24].

7.9. Agents and situations to avoid

The FMD consensus recommends caution with triptans, ergot derivatives and other vasoconstrictors, which are contraindicated if there is a history of cervical dissection or spontaneous coronary artery dissection; it advises avoiding cervical chiropractic manipulation and roller coasters, and assessing case by case prolonged neck extension, intense cervical traction, weightlifting and contact sports [15]. Smoking cessation should be strongly encouraged, because smoking is associated with renal FMD, more aneurysms and more interventions; statins are not recommended routinely without another indication; the risk of exogenous hormones (oral contraception, hormone therapy) is theoretical and without data [15]. Hypotension and hypoxia should be avoided in patients with cerebral occlusive disease, including during anaesthesia [14]. The use of ACE inhibitors in bilateral renal stenosis is the subject of the divergence described in 7.2 [12, 15].

7.10. Pregnancy, perioperative care and transition

In FMD, the consensus recommends preconception counselling with an FMD specialist and a maternal-fetal medicine specialist, especially if there has been previous dissection or poorly controlled hypertension, intensive follow-up during pregnancy with an individualised delivery plan (planned caesarean section or assisted second stage of labour in the case of dissection or aneurysm), and blood pressure monitoring in each trimester and in the immediate postpartum period, given the increased risk of pre-eclampsia in renal FMD [15]. In women with FMD, Viora-Dupont and colleagues cite frequencies of pre-eclampsia of 7.5%, HELLP syndrome of 1.3%, placental abruption of 1.4% and fetal death of 3.8%; on the basis of the severe IUGR in all pregnancies of the heterozygous mother of the French boy and the placental vascular malperfusion lesions, they propose frequent ultrasound surveillance with maternal and fetal Doppler in pregnant women heterozygous for pathogenic YY1AP1 variants and placental histology, a proposal of the authors, not a validated recommendation [7]. There are no reports of pregnancy in women with Grange syndrome in the sources consulted. In the perioperative period, extracranial arterial involvement should be documented before anaesthesia or surgery, and blood pressure should be kept within a window that protects both the kidney and the brain [14]. Transition to adult care should ensure continuity of vascular follow-up at least annually, because coronary, aortic and intestinal manifestations and progression of stenoses may appear in adulthood [6, 8, 15].

7.11. Regulatory status

Table 7.2. Comparative regulatory status

7.12. Available interventional evidence

Table 7.3. Relevant interventional studies (no randomised trial in Grange syndrome)

None of these studies allows direct comparison with Grange syndrome. The results of angioplasty in FMD and NF1 come from different populations and lesions, relative reductions in blood pressure should be read in the light of the absolute cure rate of about one third, and the densitometric response to bisphosphonates is not equivalent to a demonstrated reduction in fractures [15, 29, 42].

7.13. Developments in the last 6–12 months

Between November 2025 and October 2026 there were no clinical trials, regulatory applications, opinions or authorisations for Grange syndrome (search of ClinicalTrials.gov and the literature; a negative search does not prove non-existence) [16]. The developments are publications: the Unsel-Bolat report (2026), the first diagnosis based solely on intellectual disability and syndactyly, before any vascular manifestation [8]; Akalin's Turkish family cohort (published online on 17 April 2026), with a predominance of fractures, a dual diagnosis with CLMP and a densitometric response to bisphosphonates in three patients [9]; the "Grange-like" phenotype due to a de novo RNF213 variant (published online on 5 April 2026) [25]; the proposed nomenclature of paediatric "aorto-renal dysplasia" [43]; and the review by Robberechts and colleagues (published online on 29 April 2026), from the international consensus group, which proposes a new and more detailed classification of FMD and related diseases, imaging and proteomic biomarkers and computational fluid dynamics methods to assess the haemodynamic significance of lesions — an expert proposal, not a guideline, read only in abstract form [49]. Registries and studies of FMD without a direct link to Grange syndrome are recruiting, such as the European/international FEIRI registry (NCT04804683) and the renal FMD registry (NCT05363748) [16].

7.14. Summary of applicable recommendations and divergences

Table 7.4. Recommendations from the sources and degree of applicability

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

Grange syndrome has autosomal recessive inheritance: when both parents are heterozygous, each pregnancy has a 25% probability of an affected child, 50% of a heterozygous child and 25% of a child with neither variant [1, 6]. Consanguinity is frequent in the published families (Turkish and French families) and was suggested, without genealogical documentation, in the Brazilian family, whose parents came from the same small town and whose daughter was homozygous over a 3.3 Mb region of chromosome 1 [7, 9, 12, 24]. The offspring of a patient with a non-carrier partner will, as a rule, be heterozygous; the risk of affected offspring depends on the probability that the partner is a carrier, which cannot be estimated from the sources consulted, for lack of population frequencies of pathogenic variants. In the original family, two children of one of the affected individuals were clinically normal [1].

8.2. Cascade testing and presymptomatic diagnosis

Unlike FMD, in which the international consensus does not justify genetic testing of asymptomatic relatives because there is no specific test [15], in Grange syndrome the familial variants are known and testing of siblings allows presymptomatic affected individuals to be identified, in whom vascular surveillance can begin before stroke or severe hypertension. This is the clinical justification put forward by Unsel-Bolat and colleagues for early genetic diagnosis [4, 8]. In the French family, genetic counselling led to the identification of other members compatible with the syndrome in an extended family and to the diagnosis of the proband's father's cousin [7]. Parental testing confirms the phase of the variants (in trans) in compound heterozygosity and is necessary for the report [10, 13].

8.3. Heterozygotes

Heterozygosity does not cause Grange syndrome. The possibility that heterozygous loss-of-function variants predispose to arterial disease with reduced penetrance rests on isolated observations (the mother in the original family with late renal stenosis; one patient with FMD in a cohort of 282; the French father with a hypertensive "mini-stroke" at 30 years; transient 50% external carotid stenosis in a 9-year-old heterozygous sister) and on no positive burden analysis [6, 7, 10]. Rath and colleagues suggest that at-risk relatives could undergo regular non-invasive medical examinations, and Viora-Dupont and colleagues recommend regular follow-up of heterozygotes and maternal-fetal Doppler surveillance in heterozygous pregnant women; both are authors' proposals, without data on benefit [7, 10]. Counselling should present this uncertainty without converting it into a quantified risk.

8.4. Mosaicism

Before the gene was found, parental gonadal mosaicism was one of the explanations considered for recurrence among siblings of unaffected parents [20]. With confirmation that the parents are heterozygous in the families studied, recessive inheritance explains the recurrence, and the sources consulted do not describe somatic or germline mosaicism in YY1AP1 [6, 10].

8.5. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, molecular prenatal diagnosis is possible; in the French family, the prenatal diagnosis requested by the proband's parents confirmed an affected daughter, who had severe early IUGR and syndactyly, with normal development at 7 months [7]. IUGR, frequent in affected fetuses, is not a specific ultrasound marker [7]. Preimplantation genetic testing is an alternative for couples with known variants; the sources consulted do not report its use in this syndrome.

8.6. Counselling content and minors

Counselling should explain the variability of expression (patients with severe cerebrovascular disease in childhood and patients diagnosed in the sixth decade), the absence of genotype-phenotype correlation, the progressive nature of the arteriopathy, the need for lifelong surveillance and the absence of specific treatment [8, 10, 11]. Testing of minor siblings has direct medical benefit, because it guides vascular and bone surveillance from childhood [8, 9]; the sources consulted do not address carrier testing in healthy minors, and the uncertainty about heterozygous predisposition should be explained to families [6]. In one case, the diagnosis allowed the antihypertensive drug to be adjusted and periodic follow-up to be scheduled from the first year of life [12].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each number measures

There is no estimate of the prevalence or incidence of Grange syndrome. Orphanet assigns it the point prevalence class <1/1,000,000 worldwide, which is an upper limit and not an estimate, and the case count in the Orphanet entry itself underestimates the literature [2, 4]. The available numbers are counts of published reports: 11 patients from 6 families up to 2019 [10], 14 patients from 9 families up to the 2023 Turkish report, which added the 15th [12], 15 individuals from 10 families up to 2023 according to the French group, which added 4 [7], 22 patients with biallelic variants in the Unsel-Bolat review, which added 1 [8], and 8 affected members of a Turkish family published in 2026 [9]. Adding the 23 individuals tabulated by Unsel-Bolat to Akalin's 8, the literature consulted brings together about 31 individuals, a number that reflects rarity, probable underdiagnosis and dependence on access to sequencing, and not population frequency. In FMD, of which the syndrome is a rare monogenic cause, the estimated prevalence is about 3–4% (or 3–6% for asymptomatic FMD), and FMD accounts for 35–50% of paediatric renovascular hypertension; these figures refer to FMD as a whole and do not allow the frequency of Grange syndrome to be inferred [15, 24, 26].

9.2. Geography and ancestry

Published patients come from the USA (the original Saint Louis family; the Wallerstein patient in New Jersey), Switzerland (Zurich), Italy (Brescia), Germany (family studied in Greifswald), Canada (Halifax), Brazil, Uruguay, Turkey (Suleyman Demirel University, Diyarbakır Children's Hospital and the Unsel-Bolat report) and France (family studied in Dijon, Toulouse and Montpellier) [7–13, 20–24]. Each family has its own variants, and no founder variant has been described; the only variant shared between unrelated families is c.1903_1906del (NM_001198903.1; c.1489_1492del on MANE), present in homozygosity in the American Wallerstein patient and in compound heterozygosity in the Turkish adolescent [5, 6, 8]. Consanguinity is frequent in the Turkish families and the French family, and the three successive Turkish publications (2023–2026) may reflect the combination of consanguinity with increasing access to the exome [7, 9, 12].

The Brazilian case was studied by the Instituto da Criança of the Faculty of Medicine of the University of São Paulo in collaboration with Yokohama City University (Japan): the patient had healthy parents from Pariconha, a small town in north-eastern Brazil, and a 3.3 Mb region of homozygosity around the variant, which led the authors to suggest a common ancestor [24]. The Uruguayan case was diagnosed by genome sequencing in the URUGENOMES project of the Institut Pasteur de Montevideo [13]. The sources consulted include no patients from Portugal, and the absence of published cases does not demonstrate the absence of patients.

9.3. Special populations

Children are the group with the greatest burden of severe early events (ischaemic or haemorrhagic stroke between 15 months and 7 years, hypertension from 4 months), and paediatric vascular assessment has particular features (renal branch stenoses, need for catheter angiography, periprocedural risk) [8, 14]. In women of childbearing age, pregnancy requires planning according to the FMD consensus, and decisions on visceral aneurysms may use lower thresholds [15]. In patients with intellectual disability, communication of warning symptoms (headache, focal deficit, abdominal or chest pain) may be impaired, which reinforces scheduled surveillance [8]. Patients with late onset, such as the woman with the missense allele, may be diagnosed after years of hypertension and a stroke, which places the syndrome in the differential diagnosis in adults [11].

9.4. Reference networks and patient associations

In the European Union, the relevant reference network for the arteriopathy is VASCERN (rare multisystemic vascular diseases), through the Medium-Sized Arteries working group, which covers FMD, and the Neurovascular group; VASCERN provides decision support tools, patient pathways and information on pregnancy and family planning [17]. For the malformative and neurodevelopmental component, ERN ITHACA, and for bone fragility, ERN BOND [18, 19]. No patient association specific to Grange syndrome was found; the Fibromuscular Dysplasia Society of America (FMDSA) is an association of patients with FMD that can support families with information about the arteriopathy [50]. The European/international FMD registry (FEIRI) is recruiting [16].

10. Illustrative Clinical Case

Raggio and colleagues, from the Institut Pasteur de Montevideo, described in 2021 a Uruguayan girl, the only child of healthy non-consanguineous parents, born at 36 weeks without perinatal complications, with growth and development considered normal and cutaneous syndactyly between the 4th and 5th fingers of the left hand corrected at 1 year of age; the mother had had a previous pregnancy with oligohydramnios and growth restriction attributed to probable antiphospholipid syndrome [13]. At 6 years, hypertension, dyslipidaemia (total cholesterol 284 mg/dl, LDL 205 mg/dl, HDL 59 mg/dl, triglycerides 106 mg/dl) and subclinical hypothyroidism were diagnosed; months later she had two TIA episodes, with normal cranial CT and cervical Doppler ultrasound, without MRI [13].

At 7 years she had an ischaemic stroke, with sequelae in the supraventricular white matter of the left hemisphere and no haemorrhage on MRI. Doppler ultrasound showed severe stenosis of the right ICA, and angiography of the neck vessels revealed severe stenosis of both vertebral arteries, severe stenosis of the right ICA in the suprabulbar C1 segment and a short occlusion in the C5 segment of the left ICA, with collateral circulation (figure 1 b–e of the paper: https://pmc.ncbi.nlm.nih.gov/articles/PMC8108437/figure/Fig1/) [13]. Echocardiography showed minimal left ventricular hypertrophy with normal ejection fraction, the ocular fundus was normal and there was no lactic acidaemia, no CSF abnormality and no inherited or acquired thrombophilia. She was started on aspirin, clopidogrel, enalapril and atorvastatin. Although there was no moyamoya phenomenon, the neurosurgical team performed staged bilateral indirect cerebral revascularisation, on the left at 7 years and on the right at 8, and histopathological analysis of the arterial wall showed no significant changes [13].

Investigation for secondary hypertension (dopamine, adrenaline, noradrenaline, cortisol, ACTH, renin, aldosterone and vanillylmandelic acid) and DMSA renal scintigraphy were normal; Doppler ultrasound showed turbulent flow in the right renal artery, and angiography only minimal wall irregularities, without significant stenosis. At 9 years renovascular hypertension was diagnosed: severe stenosis of the right renal artery and moderate stenosis of the left on Doppler ultrasound and bilateral stenosis of more than 50% on angiography, without renal ischaemia or aneurysms (figure 1a of the paper); enalapril was replaced by propranolol. At 10 years balloon angioplasty was performed, with incomplete dilatation, no immediate residual stenosis and no stent, and normal renal function and acid-base balance after the procedure. At 11 years the stenosis reappeared: less than 60% and with wall irregularities on the right, moderate to severe on the left, with a peak systolic velocity of 550 cm/s; MR angiography was postponed because of the SARS-CoV-2 pandemic [13].

After years without a diagnosis, 30× genome sequencing identified compound heterozygosity for a maternally inherited single-nucleotide deletion, NM_001198903.1:c.1616del p.(Lys539ArgfsTer12) (NM_139119.3:c.1202del p.(Lys401ArgfsTer12)), and a paternal intragenic deletion of about 6.8 kb including the first coding exon, detected by inspection of coverage and by a structural variant algorithm and confirmed by junction PCR and Sanger sequencing (figure 2 of the paper: https://pmc.ncbi.nlm.nih.gov/articles/PMC8108437/figure/Fig2/) [5, 13]. Both were classified as pathogenic using ACMG criteria (PVS1, PM2, PM3). The molecular diagnosis led to recognition of brachydactyly of the hands and feet and a mild cognitive deficit that had gone unnoticed; the dyslipidaemia was attributed to polygenic hypercholesterolaemia and not to the syndrome. The patient was 13 years old at the time of publication [13].

The case illustrates four points. The arteriopathy is multi-territorial and progresses through childhood, with renal stenoses that appear or worsen years after the cerebral involvement, which corresponds to the pattern described in paediatric cerebral and systemic arteriopathies [14]. One of the variants was structural and would have escaped an analysis limited to point variants [13]. Brachydactyly and the cognitive deficit were only recognised after the genetic diagnosis, which shows the value of a targeted dysmorphological examination. Finally, some of the management in the report does not match the reference recommendations: dual antiplatelet therapy and indirect cerebral revascularisation without a moyamoya pattern are individual decisions of the team, and the statin was justified by the dyslipidaemia, not by the arteriopathy, in line with the consensus that does not recommend statins without another indication [15, 44]. Paediatric renal angioplasty with incomplete dilatation and restenosis in less than a year corresponds to what is described in other focal renal stenoses of childhood [29].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

There are no survival studies or prospectively followed cohorts; prognosis is inferred from the reports. Arterial disease is the main determinant of morbidity and mortality: about half of the tabulated patients had a stroke or TIA (10/18 and 10/19 in the two most recent reviews), about a fifth had ischaemic cardiac events and about a quarter intestinal ischaemia [7, 8]. Sudden or early deaths have been described: a sister in the original family died suddenly at 18 years, and in the French family one brother with a compatible picture died at 15 years and another at 2 years of unknown cause [1, 7]. Progressive renal failure appeared in adolescence in the French man, with a non-functioning left kidney at 13 years and left ventricular dysfunction in adulthood [7]. By contrast, the proband of the original family was 47 years old at the 2017 follow-up, with treated multi-territory, coronary and intestinal disease, and the woman with the missense allele was diagnosed at 51 years [6, 11]. Saida and colleagues emphasise that some symptoms only appear after adolescence and that periodic follow-up is necessary in all patients [24]. Intellectual disability, when present, is usually mild or borderline, and bone fragility may respond to bisphosphonates in densitometric terms [9, 12]. The vasculopathy does not follow a uniform timetable, and normal imaging at a given time does not exclude future lesions [6, 8].

11.2. Surveillance

There is no validated surveillance protocol for Grange syndrome. Table 11.1 brings together the recommendations applicable by analogy with FMD, with paediatric arteriopathies and with paediatric bone fragility; where the sources do not define an interval, the table states so.

Table 11.1. Surveillance proposed from the sources consulted

11.3. Patient and family education

The FMD consensus recommends teaching the signs of TIA, stroke and arterial dissection and the need to seek immediate care; in Grange syndrome, chest pain and abdominal pain are added, considered emergency signs by the authors of the reports [7, 15, 24]. Adherence to antiplatelet therapy, when prescribed, and to antihypertensive drugs should be checked at each visit, and transition to adult care should not interrupt surveillance [15].

12. Summary and Final Considerations

Grange syndrome is an ultra-rare autosomal recessive disease, caused by biallelic loss-of-function variants in YY1AP1, a gene without a rodent orthologue that encodes a YY1 coactivator integrated into the INO80 chromatin remodelling complex and needed for differentiation and proliferation of vascular smooth muscle cells. The core phenotype is a non-atherosclerotic, non-inflammatory stenotic-occlusive arteriopathy, angiographically similar to focal fibromuscular dysplasia, that affects the renal arteries, the internal carotid arteries and the intracranial circulation, with moyamoya-type collaterals, and often the visceral branches and the coronary arteries; renovascular hypertension and ischaemic or haemorrhagic stroke may appear from the first and second years of life. Brachydactyly, clinodactyly and syndactyly are the most constant extravascular signs and are visible at birth, whereas bone fragility, congenital heart disease, intrauterine growth restriction and learning difficulties have variable penetrance.

About 31 individuals have been published, with no prevalence estimate, no founder variant and frequent consanguinity. Diagnosis requires a genetic study that also detects intronic variants close to splice sites and intragenic deletions, because both types have already escaped exomes and microarrays, and nomenclature should be normalised to the MANE transcript NM_139119.3, distinct from the NM_001198903.1 used in most publications. Genetic diagnosis before any vascular manifestation, possible when suspicion arises from syndactyly, developmental delay or fractures, and cascade testing of siblings allow surveillance to begin before complications.

There is no specific treatment and no dedicated guideline. Management applies by analogy the international consensus on fibromuscular dysplasia — imaging from brain to pelvis, at least annual follow-up, weighed antiplatelet therapy, gradient-guided renal balloon angioplasty — and the recommendations for paediatric arteriopathies, which call for a balance between blood pressure control and cerebral perfusion and caution with interventions. Divergences persist on the use of ACE inhibitors in bilateral renal stenosis and on the balance between antiplatelet therapy and bleeding risk in a disease with haemorrhages described in childhood. Severe bone fragility may be treated with off-label intravenous bisphosphonates, on the basis of an uncontrolled observation in three patients and dosing regimens from paediatric osteoporosis. Surveillance should continue throughout life, because coronary, aortic and intestinal lesions and progression of stenoses continue to appear in adulthood.

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