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Cantú Syndrome and Related Disorders

, MD, , PhD, and , MD.

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Summary

Clinical characteristics.

Cantú syndrome and the related disorders acromegaloid facial appearance (AFA) and hypertrichosis and acromegaloid facial features (HAFF) are characterized by congenital hypertrichosis; distinctive coarse facial features (including broad nasal bridge, wide mouth with full lips and macroglossia); enlarged heart (increased ventricular mass, enlarged chambers, and normal cardiac function); and skeletal abnormalities (thickening of the calvaria, broad ribs, scoliosis, and flaring of the metaphyses). Other cardiovascular abnormalities may include patent ductus arteriosus (PDA) (in 50%), pericardial effusion (20%), and increased vascular tortuosity. Intellect is typically normal; behavioral problems can include anxiety, mood swings, obsessive-compulsive disorder, and tics.

Diagnosis/testing.

The diagnosis is established based on clinical findings and confirmed by detection of a heterozygous pathogenic variant in ABCC9 or KCNJ8.

Management.

Treatment of manifestations: Possible treatments may include shaving and (in teenagers and adults) use of depilatories or laser hair removal. Surgical closure of PDA in infancy or early childhood as needed. Pericardiocentesis and pericardial stripping as needed to treat pericardial effusion. Treatment of scoliosis with bracing and/or surgery as needed.

Surveillance: Yearly echocardiogram and electrocardiogram to monitor cardiac size and function, as well as for evidence of pericardial effusion. Monitor for scoliosis with physical examination, followed by spine radiographs as needed. Monitor for evidence of peripheral edema by history and physical examination.

Evaluation of relatives at risk: If the pathogenic variant in an affected family member is known, relatives at risk who are suspected of having Cantú syndrome can be offered molecular genetic testing to clarify their genetic status. Family members who are affected should be evaluated and monitored for cardiac manifestations, scoliosis, and lymphedema.

Pregnancy management: A pregnancy in which the fetus has Cantú syndrome warrants monitoring for polyhydramnios and macrosomia.

Genetic counseling.

Cantú syndrome and the related disorders AFA and HAFF are inherited in an autosomal dominant manner. Most cases of Cantú syndrome result from a de novo pathogenic variant; less information is available on the related disorders. Each child of an individual with Cantú syndrome or a related disorder has a 50% chance of inheriting the pathogenic variant and being affected. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.

GeneReview Scope

Cantú Syndrome and Related Disorders: Included Phenotypes
  • Cantú syndrome 1
  • Acromegaloid facial appearance
  • Hypertrichosis with acromegaloid facial features
1.

For synonym see Nomenclature.

Diagnosis

No formal diagnostic criteria for Cantú syndrome and related disorders have been established.

Suggestive Findings

Cantú syndrome or a related disorder should be suspected in individuals with a combination of the following:

  • Congenital hypertrichosis: excess hair growth on scalp, forehead, face, back, and limbs. See Figure 1 and Figure 2.
  • Craniofacial dysmorphic features: coarse facial features, epicanthal folds, broad nasal bridge, anteverted nares, long philtrum, macroglossia, wide mouth, and full lips (see Figure 1). The palate may be high arched and/or narrow. The gingiva may be thickened. Anterior open bite may be present as well.
  • Enlarged heart (see Figure 3 and Figure 4) and additional cardiovascular abnormalities that may include patent ductus arteriosus, pericardial effusion, and aortic aneurysm
  • Characteristic skeletal abnormalities: thickening of the calvaria (see Figure 3), broad ribs, platyspondyly, ovoid vertebral bodies, scoliosis, narrow thorax and shoulders, pectus carinatum, hypoplastic ischium and pubic bones, Erlenmeyer-flask-like long bones with metaphyseal flaring (see Figure 3 and Figure 4), narrow obturator foramen, and coxa vara. Generalized osteopenia, delayed bone age, and craniosynostosis have also been described.
Figure 1. A, B, C.

Figure 1

A, B, C. Facial appearance showing hirsutism of the forehead with low frontal hairline and coarse features D, E. Lateral views showing excess hair on the cheeks F. Hirsutism of the arms A, D: a woman age 40 years B, E: a girl age 16 years C, F: a girl (more...)

Figure 2. A.

Figure 2

A. Narrow thorax and pectus carinatum deformity B,C. Hirsutism of the lower back (B) and forearms(C) A, B: a girl age 11 years C: a girl age 16 years From Grange et al [2006]; used with permission from Am J Med Genet

Figure 3. A.

Figure 3

A. Chest x-ray showing marked cardiomegaly B. Lateral skull x-ray showing thickened calvarium C. Erlenmeyer flask deformity with metaphyseal flaring of the distal radius (arrow) D. Metaphyseal flaring of the distal femur (arrow) All images are from a (more...)

Figure 4. A.

Figure 4

A. Chest x-ray showing cardiomegaly B. Early metaphyseal flaring of the distal radius (arrow) Both images are from a girl age 16 years. From Grange et al [2006]; used with permission from Am J Med Genet

Establishing the Diagnosis

The diagnosis of Cantú syndrome (or a related disorder) is established in a proband with characteristic clinical features and is confirmed by detection of a heterozygous pathogenic variant in ABCC9 or KCNJ8 [Brownstein et al 2013, Cooper et al 2014].

Individuals with the related conditions acromegaloid facial appearance (AFA) syndrome and hypertrichosis with acromegaloid facial features (HAFF) syndrome have also been found to have a pathogenic variant in ABCC9.

Table 1.

Summary of Molecular Genetic Testing Used in Cantú Syndrome and Related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
ABCC9Sequence analysis 230/35 persons reported in the literature who have undergone molecular testing 3
Deletion/duplication analysis 4Unknown, none reported 5
KCNJ8Sequence analysisTwo cases 6
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.
4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

ABCC9 deletion/duplication has not been reported in Cantú syndrome. Because the syndrome results from gain-of-function pathogenic variants, deletions/duplications are not expected to occur, although it is conceivable that duplication could be causative.

6.

Clinical Characteristics

Clinical Description

To date, about 50 individuals have been reported with Cantú syndrome and about 12 individuals have been reported with the related disorders acromegaloid facial appearance (AFA) syndrome and hypertrichosis with acromegaloid facial features (HAFF) syndrome.

In earlier reports, the diagnosis of Cantú syndrome, AFA syndrome, and HAFF syndrome was based on clinical findings only.

Twenty-eight of the 35 individuals with Cantú syndrome undergoing molecular genetic testing to date have been found to have a heterozygous pathogenic variant in ABCC9 [Harakalova et al 2012, van Bon et al 2012, Hiraki et al 2014, Park et al 2014]; two were found to have a heterozygous pathogenic variant in KCNJ8 [Brownstein et al 2013, Cooper et al 2014]. A heterozygous ABCC9 pathogenic variant was identified in one individual with AFA syndrome and one with HAFF syndrome [Czeschik et al 2013].

Note: Some individuals with Cantú syndrome have been reported twice: first when the diagnosis was based on clinical findings and subsequently when the diagnosis was confirmed molecularly. Among the individuals reported by van Bon et al [2012], eight of 14 had been reported before; among those reported by Harakalova et al [2012], seven of 16 had been reported before.

Because the molecular basis of these disorders has only recently been discovered, understanding about the breadth of the phenotype and its natural history is currently limited, but is expected to evolve over time. To date no major differences have been identified in those with Cantú syndrome based on a strictly clinical diagnosis compared to those with a molecularly confirmed diagnosis. The data are too limited to make any statement about AFA and HAFF syndromes.

Cantú Syndrome

Many pregnancies with a fetus with Cantú syndrome are complicated by polyhydramnios, leading in some instances to repeated amniotic fluid reductions as well as preterm labor and delivery.

Newborns. All newborns with Cantú syndrome have hypertrichosis with thick scalp hair and excessive hair growth on the forehead, face, back, and extremities. Some have thick and/or curly eyelashes. The hypertrichosis usually persists over time.

Many newborns have macrosomia (large birth weight and birth length). Ultimate adult height is usually within the normal range; however, short stature has been seen in a few individuals.

Macrocephaly, often present at birth, typically persists throughout life. Some individuals who do not have macrocephaly at birth have developed progressive macrocephaly in childhood.

Generalized edema at birth (observed on occasion) usually resolves spontaneously.

Skeletal abnormalities are usually asymptomatic and do not require any intervention. In a few patients, scoliosis has required bracing and surgery.

Cardiac features include the following:

  • Cardiac enlargement, with increased ventricular mass and enlarged chambers of the heart, often present at birth. Despite the increased cardiac muscle mass, cardiac function is typically normal and ventricular contractility is normal on imaging studies [Grange et al 2006]. Some patients note exercise intolerance, but others have been able to participate in organized sports without difficulty.
  • Patent ductus arteriosus (PDA) in 50% (and described as extremely large in some), often requiring surgical closure in infancy or early childhood
  • Bicuspid aortic valve with and without stenosis
  • Pericardial effusion in about 20% of affected individuals. Small pericardial effusions may be asymptomatic; large fluid accumulations result in symptoms such as exercise intolerance and require intervention.
  • Aortic aneurysm reported in one individual with an ABCC9 pathogenic variant, requiring surgical intervention [Hiraki et al 2014]

Vascular abnormalities include tortuous retinal vessels and multiple tortuous pulmonary arteriovenous communications [Scurr et al 2011]. Vascular abnormalities were particularly notable in one child with a pathogenic variant in KCNJ8 [Brownstein et al 2013] (see under Less frequent features below). Abnormal vasculature in the brain has also been seen in individuals with a pathogenic variant in ABCC9 [Grange, unpublished].

Pulmonary hypertension has been reported in several infants and young children; however, the natural history is not well understood [Cantú et al 1982, Robertson et al 1999, Lazalde et al 2000, Kobayashi et al 2010, Scurr et al 2011]. In one child, pulmonary hypertension secondary to partial pulmonary venous obstruction was associated with severe mitral valve regurgitation that spontaneously resolved by age eight years [Kobayashi et al 2010]. A patient reported by Scurr et al [2011] responded to steroid therapy and eventually improved. More recently, a patient with progressive -and ultimately fatal - pulmonary hypertension was reported [Park et al 2014].

Generalized edema, which may be present at birth, spontaneously resolves. Subsequently, edema involving the lower extremities and occasionally the arms and hands may develop over time, usually in adolescence or early adulthood. In one individual, lymphangiography demonstrated dilated lymphatic vessels in the legs with delayed lymphatic drainage [García-Cruz et al 2011]. In contrast, lymphatic studies were normal in another individual [Scurr et al 2011]. Therefore, it is unclear at this time whether the observed swelling is edema or lymphedema.

Intellect. Although the majority of affected individuals have normal intellect, mild learning disabilities and/or developmental delays have been observed, including delay in acquisition of early motor milestones (most likely related to decreased muscle tone) and delay in speech development. Ultimately, most affected individuals attend regular schools and some are described as having a high IQ [Scurr et al 2011].

Behavioral problems have been reported in a few individuals, including anxiety, mood swings, obsessive-compulsive disorder, and tics [Scurr et al 2011].

Features of a connective tissue abnormality are observed in many individuals with Cantú syndrome, including wrinkled or loose skin especially at birth, deep palmar and plantar creases, and joint hyperextensibility. Some have decreased subcutaneous fat with the appearance of a muscular build in childhood.

Less frequent features include:

  • Umbilical hernia
  • Pyloric stenosis
  • Gastroesophageal reflux
  • Increased risk for upper gastrointestinal bleeding
  • Poor intestinal motility [Grange, unpublished]
  • Ptosis
  • Craniosynostosis involving the sagittal and coronal sutures in one individual [Hiraki et al 2014]
  • Increased frequency of infections, raising the possibility of immune dysfunction; two individuals with low IgG levels responded well to IVIG infusions [Scurr et al 2011; Grange, unpublished].
  • Growth hormone deficiency in a few individuals [Grange, unpublished]
  • Rarely, autism spectrum features [Scurr et al 2011]

The two individuals reported thus far with a pathogenic variant in KCNJ8 had many typical clinical features seen in Cantú syndrome [Brownstein et al 2013, Cooper et al 2014]. The patient reported by Brownstein et al had the following additional abnormalities:

  • Brain MRI: cerebral atrophy and thin corpus callosum
  • Cerebral vasculature: tortuous arteries in the circle of Willis and internal carotids, multiple tortuous venous collaterals and lack of flow in the inferior sagittal sinus.
  • Systemic vasculature: dilated aortic root, dilated hepatic and celiac arteries, dilated and tortuous intrahepatic arteries and veins, and multiple aorto-pulmonary and bronchial collateral vessels.

Related Disorders

Acromegaloid facial appearance (AFA) syndrome, first reported by Hughes et al [1985], is characterized by coarse facial features. Pericardial effusion has been reported in a few cases. Five additional cases/families demonstrating autosomal dominant inheritance were described [Dallapiccola et al 1992, da-Silva et al 1998, Zelante et al 2000, Stratakis et al 2001, Kini & Clayton-Smith 2004]. Another family with AFA syndrome was reported by Ghazi et al [2013], but no genetic testing was performed.

Hypertrichosis with acromegaloid facial features (HAFF) syndrome, reported first as an association by Irvine et al [1996], is characterized by coarse acromegaloid facial features with hypertrichosis. Subsequently, additional cases/families have been described. Based on a review of the reported cases of generalized hypertrichosis listed in OMIM, it appears likely that more than one genetic entity has been included. While the findings in some resemble Cantú syndrome [Irvine et al 1996, Czeschik et al 2013], the phenotype in others is different with more severe and generalized hypertrichosis. The condition termed generalized hypertrichosis terminalis with gingival hyperplasia has been linked to 17q24.2-q24.3 [Sun et al 2009]; thus, this group likely has a genetic cause that is not related to mutation of ABCC9 or KCNJ8.

When Czeschik et al [2013] reported two individuals – one with AFA syndrome and the other with HAFF syndrome – with gain-of-function ABCC9 pathogenic variants previously reported in persons with typical Cantú syndrome (see Molecular Genetics), it became apparent that these two phenotypes represent the milder end of the phenotypic spectrum caused by mutation of ABCC9. Of note, in addition to hypertrichosis in the individual with HAFF and coarse facial features in both, each had some features of Cantú syndrome.

  • In the child reported to have AFA syndrome, the pregnancy was complicated by polyhydramnios, and the child had an atrial septal defect, mild pulmonary stenosis, a meningeal aterio-venous malformation, deep palmar creases, and scoliosis.
  • The child reported to have HAFF syndrome had edema at birth, a PDA and an aortopulmonary collateral artery (which required occlusion by coil embolization), gingival hypertrophy, and hyperextensible joints.

Genotype-Phenotype Correlations

Current information about genotype-phenotype correlation in Cantú syndrome and related disorders is limited.

Penetrance

Although penetrance for Cantú syndrome and related disorders in familial cases reported thus far appears to be complete, molecular genetic testing has only been performed in a few families.

Males and females are equally affected.

Nomenclature

Cantú syndrome may also be referred to as hypertrichotic osteochondrodysplasia.

Prevalence

The prevalence of Cantú syndrome is unknown. To date, about 50 individuals have been reported with Cantú syndrome and about 12 individuals have been reported with the related disorders acromegaloid facial appearance (AFA) syndrome and hypertrichosis with acromegaloid facial features (HAFF) syndrome (see Clinical Description).

Increased awareness of these clinical phenotypes may lead to improved recognition and, thus, a higher prevalence.

Differential Diagnosis

Lysosomal storage diseases. Many individuals with Cantú syndrome are initially thought to have a lysosomal storage disorder due to the presence of coarse facial features and hirsutism. Some of the skeletal features, such as thickening of the ribs, can also be confused with the radiologic features of the mucopolysaccharidoses. Specifically, mucopolysaccharidosis type I (Hurler syndrome), mucopolysaccharidosis type II (Hunter syndrome), mucopolysaccharidosis type IVA (Morquio syndrome A), mucolipidosis III alpha/beta, mucolipidosis III gamma, and alpha-mannosidosis could potentially be confused with Cantú syndrome prior to additional testing.

Beckwith-Wiedemann syndrome (BWS). Some individuals with Cantú syndrome have been previously diagnosed with Beckwith-Wiedemann syndrome due to the clinical findings of neonatal macrosomia, coarse facial features with macroglossia, and umbilical hernia.

Congenital hypothyroidism. The macroglossia and hirsutism that can be seen in congenital hypothyroidism may overlap with features of Cantú syndrome.

Acromegaly. The macrocephaly, coarse facial features, and tall stature in some adults with Cantú syndrome have been confused with acromegaly due to excess human growth hormone.

Berardinelli-Seip congenital lipodystrophy. The muscular build with decreased subcutaneous fat noted in some children with Cantú syndrome in association with cardiomegaly and acromegaloid facial features has led to consideration of a diagnosis of Berardinelli-Seip congenital lipodystrophy.

Hypertrophic cardiomyopathy or dilated cardiomyopathy. The cardiomegaly seen in Cantú syndrome may lead to a diagnosis of hypertrophic and/or dilated cardiomyopathy. However, unlike individuals with other forms of familial cardiomyopathy, persons with Cantú syndrome have normal myocardial function (despite the enlargement of the cardiac chambers) as well as other non-cardiac findings.

Minoxidil treatment may lead to coarsening of facial features and hirsutism that has been called “pseudoacromegaly” [Nguyen & Marks 2003]. Minoxidil, an antihypertensive, acts by opening ATP-dependent potassium channels, resulting in smooth muscle relaxation and a subsequent drop in blood pressure. This physiologic effect of minoxidil is equivalent to a gain-of-function pathogenic variant in ABCC9. Minoxidil has long been associated with hair growth and is used topically to treat scalp hair loss. When taken orally, it may cause generalized hirsutism, progressive coarsening of the facial features, and pericardial effusions, all of which can resemble the clinical features of Cantú syndrome.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Cantú syndrome and related disorders, the following evaluations are recommended:

  • Cardiology evaluation with echocardiogram and electrocardiogram
  • Skeletal survey to assess for the associated bone abnormalities
  • Evaluation for scoliosis
  • Clinical genetics consultation

Treatment of Manifestations

Consider referral to a dermatologist for discussion of treatment options for hypertrichosis. Possible treatments may include shaving and, in teenagers and adults, use of depilatories or laser hair removal.

Patent ductus arteriosus (PDA) often requires surgical closure in infancy or early childhood. Of note, the PDA in Cantú syndrome is frequently described as being very large.

Pericardial effusion sometimes requires pericardiocentesis and ultimately pericardial stripping to prevent reaccumulation of the effusion.

Scoliosis may require bracing or surgical correction.

Standard management for peripheral edema, including compression stockings, is indicated.

Surveillance

If cardiac abnormalities are present, follow-up intervals should be determined by the cardiologist according to the specific clinical manifestations. Otherwise, yearly echocardiogram and electrocardiogram are recommended to monitor cardiac size and function, as well as for evidence of pericardial effusion. These studies should be started in infancy, or as soon as the diagnosis is made, and continued throughout life.

Spine radiographs to assess for scoliosis should be performed if there is concern based on physical examination. If scoliosis is present, continued monitoring by an orthopedist is recommended.

Consider brain MRI with magnetic resonance angiogram (MRA) and magnetic resonance venography (MRV) to evaluate persistent headaches or other neurological symptoms, given the increased risk for cerebral vascular abnormalities.

Affected individuals should be monitored for edema –which often develops in adolescence or early adulthood- by reviewing the medical history regarding swelling of the limbs, and by physical examination.

Evaluation of Relatives at Risk

If the pathogenic ABCC9 or KCNJ8 variant in an affected family member is known, relatives at risk who are suspected of having Cantú syndrome can be offered molecular genetic testing to clarify their genetic status. Family members who are affected should be evaluated (see Evaluations Following Initial Diagnosis and Surveillance).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy of a fetus with Cantú syndrome warrants monitoring for:

  • Polyhydramnios. The cause of polyhydramnios is unknown. In some instances, severe polyhydramnios has required serial amniotic fluid reductions and has led to premature labor and delivery.
  • Macrosomia. It is unknown if fetal size warrants special consideration at the time of delivery.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Cantú syndrome and the related disorders acromegaloid facial appearance (AFA) syndrome and hypertrichosis and acromegaloid facial features (HAFF) syndrome are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with Cantú syndrome, AFA syndrome, or HAFF syndrome have an affected parent.
  • Although a few families have been reported, to date most cases of Cantú syndrome have resulted from a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown.
  • Several multigenerational families with AFA have been reported.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo mutation in the proband. Germline mosaicism has been suggested to explain the affected sibs reported by Cantú et al [1982].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although some individuals diagnosed with Cantú syndrome or a related disorder have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members. (2) Although not reported, it is theoretically possible that if the parent is the individual in whom the pathogenic variant was first identified, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected and/or has an ABCC9 or KCNJ8 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. The phenotype, age of onset, and severity are not predictable.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with Cantú syndrome or a related disorder has a 50% chance of inheriting the pathogenic variant. The phenotype, age of onset, and severity are not predictable.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

A priori increased risk for Cantú syndrome and related disorders. If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing. The phenotype, age of onset, and severity are not predictable based on results of prenatal molecular genetic testing.

No a priori increased risk for Cantú syndrome. Since Cantú syndrome usually results from a de novo pathogenic variant and since the etiology of polyhydramnios is diverse, the diagnosis of Cantú syndrome or a related disorder is not usually suspected prenatally and is typically made after birth. However, the combination of fetal macrosomia and polyhydramnios should lead to consideration of Cantú syndrome.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for Cantú Syndrome have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Cantú syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Cantú syndrome (View All in OMIM)

239850CANTU SYNDROME
600935POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 8; KCNJ8
601439ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 9; ABCC9

Molecular Genetic Pathogenesis

ABCC9 encodes the ATP-binding cassette transporter sub-family C member 9 (commonly referred to as the SUR2 protein), a member of the superfamily of ATP-binding cassette (ABC) transporters, and functions as a subunit of ATP-sensitive potassium channels in cardiac, skeletal, and smooth muscle, as well as endothelial and other tissues.

Alternative splicing of this gene results in several products, two of which result from differential use of two terminal exons to generate the protein isoforms: SUR2A and SUR2B [Nichols 2006]. Further functional analyses to identify downstream mechanisms and interacting proteins are important to the understanding of the role of ABCC9 in hair growth, craniofacial abnormalities, and cardiovascular complications [Nichols et al 2013]. One such interacting protein, Kir6.1, complexes with SUR2 proteins to form ATP-sensitive potassium channels. Recently, a pathogenic variant in KCNJ8, which encodes Kir6.1, has been identified in an individual with Cantú syndrome.

ABCC9

Gene structure. Both ABCC9 transcript variants comprise 38 exons. The transcript variant NM_005691.2 encodes the SUR2A isoform, while NM_020297.2 encodes SUR2B. These transcripts only differ in the last exon. All pathogenic variants identified thus far affect both transcripts. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Several uncommon (<0.3% minor allele frequency) single nucleotide variants (SNVs) have been found in the ABCC9 coding sequence, including: the NM_005691.2 missense variants c.3409G>A (p.Val1137Ile), c.2200G>A (p.Val734Ile); the coding synonymous variants (no change in amino acid residue indicated by = sign) c.1848C>T (p. Asp616=), c.1056C>T (p.Tyr352=), c.789C>T (p.Cys263=); and multiple rare variants reported from well-phenotyped US populations.

Pathogenic variants. ABCC9 missense pathogenic variants have been identified in 27 individuals with Cantú syndrome, one individual with AFA syndrome, and one individual with HAFF syndrome. In total, 14 different pathogenic variants have been reported to date [Harakalova et al 2012, van Bon et al 2012, Czeschik et al 2013, Hiraki et al 2014], some of which have been confirmed to result in gain-of-function potassium channels generated by the encoded SUR2 subunit.

Czeschik et al [2013] identified ABCC9 missense pathogenic variants in two individuals with the related conditions, acromegaloid facial appearance (AFA) syndrome (NM_005691.2:c.3347G>A, p.Arg1116His) and hypertrichosis with acromegaloid facial features (HAFF) syndrome (NM_005691.2:c.3461G>A, p.Arg1154Gln), which the authors believe represent the mild end of the spectrum of Cantú syndrome. These variants have also been found in individuals with Cantú syndrome (see Table 2).

Table 2.

ABCC9 Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Benignc.3409G>Ap.Val1137Ile 1NM_005691​.2
NP_005682​.2
c.2200G>Ap.Val734Ile 1
Pathogenicc.178C>Tp.His60Tyr 2
c.621C>Ap.Asp207Glu 2
c.1138G>Tp.Gly380Cys 2
c.1295C>Tp.Pro432Leu 2
c.1433C>Tp.Ala478Val 3
c.3058T>Cp.Ser1020Pro 2
c.3116T>Cp.Phe1039Ser 2
c. 3128G>Ap.Cys1043Tyr 3
c.3161C>Ap.Ser1054Tyr 2
c.3347G>Ap.Arg1116His 2, 4
c.3346C>Tp.Arg1116Cys 2
c.3460C>Tp.Arg1154Trp 2 3
c.3461G>Ap.Arg1154Gln 2, 3, 4
c.3605C>Tp.Thr1202Met 5
c.4385C>Gp.Ala1462Gly 6

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Presumed non-pathogenic. Mutant protein has not been analyzed.

2.

Cantú syndrome-associated pathogenic variants reported in Harakalova et al [2012]

3.

Cantú syndrome-associated pathogenic variants reported in van Bon et al [2012]

4.

AAF/HAFF-associated pathogenic variants reported in Czeschik et al [2013]

5.

Cantú syndrome-associated pathogenic variant reported in Hiraki et al [2014]

6.

Cantú syndrome-associated pathogenic variant reported in Park et al [2014]

Normal gene product. SUR2 is a large transmembrane protein member of the C-subfamily of ATP-binding cassette (ABC) family of proteins. The protein comprises three transmembrane domains (TM0, TM1, TM2), with two cytoplasmic nucleotide-binding folds (NBF1 following TM1 and NBF2 at the C-terminus, following TM2) [Nichols 2006].

Co-expression of the sulfonylurea receptor SUR2 (ABCC9) with the pore-forming inward rectifier proteins Kir6.1 (KCNJ8) or Kir6.2 (KCNJ11) in mammalian cell lines generates ATP-sensitive potassium (KATP) channels with properties corresponding to those found in vascular smooth muscle cells or cardiac ventricular myocytes, respectively [Flagg et al 2010]. These potassium channels are inhibited by intracellular ATP interaction with the channel subunit and activated by MgADP interaction with NBF1 and NBF2 of the SUR subunit. Thus, activity depends on the metabolic state of the cell, such that channels tend to activate under conditions of metabolic compromise.

Transgenic manipulation and gene knockout in mice have elucidated the essential roles of Kir6.1 subunits in generating vascular KATP channels, SUR2A subunits in generating cardiac ventricular channels, and SUR2B in generating vascular smooth muscle KATP channels; however, details of expression in other cell types and understanding of the physiologic role of these KATP channels remain incomplete. Animals completely lacking Kir6.1 or SUR2 protein have a weak hypertensive phenotype, accompanied by coronary vasospasm that mimics human Prinzmetal angina [Flagg et al 2010]. Animals expressing Kir6.1 gain-of-function variants in smooth muscle have a hypotensive phenotype [Li et al 2013].

In addition to the alternate splicing of exon 38, there is evidence for multiple splice variants in SUR2, including variants that lack the full complement of exons [Ye et al 2009]; however, the functional significance of such splicing variants and any proteins they encode remains unclear.

It should be noted that a different gene pair (ABCC8, KCNJ11) encodes the SUR1 regulatory subunit and Kir6.2 pore-forming subunit of the neuroendocrine KATP channel. Loss-of-function and gain-of-function pathogenic variants in ABCC8 or KCNJ11 underlie familial hyperinsulinism and neonatal diabetes mellitus respectively. While the molecular functions of SUR1 and SUR2 (and of Kir6.1 and Kir6.2) are very similar, the overlap in expression of the two pairs of proteins may be minimal since the features of Cantú syndrome and neonatal diabetes mellitus do not obviously overlap.

Abnormal gene product. Although the ABCC9 missense pathogenic variants that cause Cantú syndrome are located throughout the protein, several amino acid residues appear to be mutational ‘hot spots’ because the same de novo pathogenic variant was identified in multiple unrelated affected individuals [van Bon et al 2012, Harakalova et al 2012]. Some of these pathogenic variants have been confirmed to have gain-of-function effects on the SUR2 protein.

KCNJ8

Gene structure. KCNJ8 comprises three exons, and a transcript of 2406 bp that encodes a protein of 424 amino acids. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. SNVs found in the KCNJ8 coding sequence include the uncommon (<0.3% minor allele frequency) missense variant NM_004982.3:c.1265C>T (p.Ser422Leu) (see also rs72554071) and multiple additional rare variants.

Pathogenic variants. Two individuals with Cantú syndrome were found to have a de novo heterozygous KCNJ8 pathogenic variant: c.193G>A in one individual [Brownstein et al 2013] and c.526T>A in the other [Cooper et al 2014].

Table 3.

KCNJ8 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.193G>Ap.Val65MetNM_004982​.3
NP_004973​.1
c.526T>Ap.Cys176Ser

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. KCNJ8 (NM_004982.3) encodes the pore forming subunit of one of the ATP-sensitive inwardly rectifying potassium (KATP) channels, known as Kir6.1. Kir6.1 channels complex at 4:4 stoichiometry with the sulfonylurea receptor SUR1 and SUR2 protein isoforms (encoded by ABCC9) to form ATP-sensitive potassium channels in smooth muscle, endothelium, and other tissues.

Abnormal gene product

  • The mechanism of action of the abnormal p.Val65Met protein is unknown.
  • The p.Cys176Ser mutant Kir6.1 channels exhibit significantly higher activity than wild-type channels due to reduced ATP sensitivity [Cooper et al 2014].

References

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Suggested Reading

  • Engels H, Bosse K, Ehrbrecht A, Zahn S, Hoischen A, Propping P, Bindl L, Reutter H. Further case of Cantú syndrome: Exclusion of cryptic subtelomeric chromosome aberrations. Am J Med Genet. 2002;111:205–9. [PubMed: 12210352]

Chapter Notes

Author Notes

Dorothy K Grange, MD

Colin G Nichols, PhD

Dr.Nichols’ research is focused on the biology of ion channels, with emphasis on the molecular basis of potassium channel activity and the role of potassium channels in physiology and disease. Using various molecular biological and biophysical approaches, his laboratory is developing detailed understanding of the structural basis of channel activity, and animal models to understand the role of potassium channels in disease processes including diabetes, cardiovascular pathology and arrhythmias, and epilepsy.

Gautam K Singh, MD

Revision History

  • 2 October 2014 (me) Review posted live
  • 2 October 2013 (dkg) Original submission
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