Antley-Bixler syndrome

Many, but not all, girls who have Antley-Bixler syndrome (ABS) with genital anomalies and disordered steroidogenesis need corrective surgery. For those who do, some parents chose to have this done early in infancy. In some cases, due to urine reflux (back up) into the bladder or the kidneys, surgical repair needs to be done early in life. Other parents postpone surgery until their daughter is old enough to make the decision herself. To learn more about genital surgery in girls with Antley-Bixler syndrome, visit the CARES Foundation.

One main symptom of Antley-Bixler syndrome (ABS) is craniosynostosis. Craniosynostosis is premature closure of skull bones causing problems with normal brain and skull growth. Depending on the form of ABS, the individual will have either reduced activity of the enzyme cytochrome P450 oxidoreductase or increased activity of FGFR2 protein signaling. The cytochrome P450 oxidoreductase enzyme is needed for the production of cholesterol. A shortage of cholesterol leads to abnormal fusion of bones, including skull bones. The FGFR2 protein signals immature cells in the developing embryo to become bone cells. Changes to the FGFR2 gene causes the FGFR2 protein to overactivate leading to premature fusion of bones in the skull.

Ambiguous genitalia is often associated with one form of Antley-Bixler syndrome. In females, ambiguous genitalia can present as enlarged clitoris and/or fused and underdevelopment labia. Males can present with a small penis and/or undescended testes. These symptoms in individuals with this condition are due to deficiencies in steroid hormone production, including testosterone and estrogen. These hormones are essential for normal sexual development and reproduction.

Get more detailed information about how changes in the POR gene cause symptoms by visiting the Genetics Home Reference or GeneReviews.

Antley-Bixler syndrome (ABS) without genital anomalies and disordered steroidogenesis is an autosomal dominant condition. Genes exist in pairs and autosomal dominant conditions occur when a change to one copy of a gene is enough to cause the condition. This type of ABS may be the result of a new change in that individual or it may be inherited from an affected parent. Therefore, it is recommended to evaluate parents through clinical, radiographic, and molecular genetic evaluation. Once the status of the parents is known other family members’ risk can be determined. If a parent is affect, his or her family members are at risk and may consider testing. Furthermore, if the change in the gene came from an affected parent, each child of the parent will have a 50% chance of having this condition. Prenatal testing is available is mutation is known.

Discuss with your doctor about any concerns you have or for a referral to a medical geneticist, genetic counselor, and other medical specialist.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

Antley-Bixler syndrome (ABS) with genital anomalies and disordered steroidogenesis is an autosomal recessive condition. Genes exist in pairs and autosomal recessive conditions occur when there are changes to both gene copies. Individuals with one altered gene, referred to as carriers, do not develop the condition and typically do not have any symptoms. Parents of an individual with this type of ABS are obligated carriers for the condition. Siblings of the affect individual have a 50% chance of being a carrier of this conditions and, therefore, may consider testing.

Discuss with your doctor about any concerns you have or for a referral to a medical geneticist, genetic counselor, and other medical specialist.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

Although, as of January 2019, studies on the natural course of Antley-Bixler syndrome (ABS) are currently lacking, the prognosis is dependent on the severity of the skeletal and craniofacial malformation. Very severe skeletal malformations can cause stillbirths or death shortly after birth. Many individuals with ABS die in infancy from respiratory compromise. For individuals with mild malformation, their prognosis improves with age. However, with effective airway management, many individuals will have a reasonably good prognosis.

A blood (1.5 – 3.0 mL) or a saliva (1-2 mL) sample can be used for Antley-Bixler syndrome genetic testing.

Discuss with your doctor about any concerns you have or for a referral to a medical geneticist and other medical specialist.

To discuss arranging genetic testing for Antley-Bixler Syndrome, contact a local genetic counselor. Genetic counselors can be found on the National Society of Genetic Counselors website.

After a diagnosis of Antley-Bixler syndrome (ABS) is made, an evaluation is recommended to determine the extent of disease and needs of the individual. Referral to appropriate specialist for evaluation include endocrinology, clinical genetics, neurosurgery, otolaryngology, and cardiology. Individuals with ABS without genital anomalies and disordered steroidogenesis should be seen by a specialist pediatric endocrine center throughout childhood to closely monitor their development and adjust steroid supplementation. ABS is a craniosynostosis syndrome which benefits from the multidisciplinary team approach practiced in most craniofacial clinics. The specialists usually include plastic surgeons, neurosurgeons, otolaryngologists, and dentists as well as audiologists, speech pathologists, developmental pediatricians, social workers, and medical geneticists. This team of specialist will work closely with you and your child to customize the treatment plan to your child’s specific needs.
 
Consult with your doctor or medical geneticist to find specialists in your area. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website.

ABS

Antley-Bixler syndrome (ABS) is a rare genetic disorder characterised by skeletal malformations, especially craniofacial abnormalities. There are two forms of ABS: ABS with genital anomalies and disordered steroidogenesis, and ABS without genital anomalies and disordered steroidogenesis. These forms are two distinct disorders caused by mutations in the POR gene or the FGFR2 gene, respectively.

When a change is found in the FGFR2 or POR gene through genetic testing, there are three classifications for changes: pathogenic, benign, or variant of unknown significance (VUS). A pathogenic change means the change to the gene is disease causing and has typically been reported in many individuals with the ABS. A benign change means the change to the gene does not cause disease and has typically been reported in many healthy individuals. A VUS is a change to the gene, that at this present time, it is unclear whether the change is harmful or not. Typically, a VUS is a change that has not been reported many times or has never been reported and, therefore, there is not enough evidence to support a classification of the change. Over time, VUS can be reclassified to either pathogenic or benign if more cases of the change are found.

A genetic counselor can help you learn more. Genetic counselors can be found on the National Society of Genetic Counselors website.

Depending on what primary symptoms an individual with Antley-Bixler syndrome (ABS) has, there are secondary complications that should be monitored for. In individuals with severe protruding eyes (proptosis), lubrication is often required to prevent exposure keratopathy, which is damage to the cornea due to prolong exposure of eyes to the outside environment. If surgery was performed to correct premature closure of skull bones (craniosynostosis), monitoring of intracranial pressure is needed. If pressure increases, re-operation may be required. Continuous surveillance for hydrocephalus (too much cerebrospinal fluid in the brain) is also required in people with ABS. Ventriculoperitoneal shunt insertion may be needed to relieve pressure on brain from fluid accumulation.

Discuss with your doctor about any concerns you have or for a referral to a medical geneticist and other medical specialist.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website.

There are two genetically distinct forms of Antley-Bixler syndrome (ABS). ABS with genital anomalies and disordered steroidogenesis is caused by changes (mutations) to the POR gene, which encodes instructions to make the enzyme cytochrome P450 oxidoreductase. This enzyme is important in the formation of steroid hormones, such as testosterone and estrogen. Changes to the POR gene decreases activity of the cytochrome P450 oxidoreductase leading to the disruption of steroid hormone production. Consequently, sexual development problems occur before birth and at puberty.

The enzyme cytochrome P450 oxidoreductase also plays a role in cholesterol production; which is also needed in the production of steroid hormones and in bone formation and growth. Disruptions in the POR gene can cause abnormal bone growth and fusion of bones.

The alternative form; ABS without genital anomalies and disordered steroidogenesis, is caused by changes to the FGFR2 gene, which provides instructions to make a protein called fibroblast growth factor receptor 2. This protein is involved in many biological processes, especially during embryonic development. For example, it plays a role in cell division, regulation of cell growth and maturation, and formation of blood vessels. It also contributes to bone growth by signalling cells in the developing embryo to become bones cells. Changes to the FGFR2 gene can cause increased signalling by FGFR2 protein, which causes premature closure of the bones in the skull.

Learn more about how the POR and FGFR2 gene works by visiting the Genetics Home Reference

For children who have Antley-Bixler syndrome (ABS) with genital anomalies and disordered steroidogenesis, it is best to discuss medication changes with your medical team. During a mild illness in which the child is able to keep hydrated, steroid doses are increased. Children who are vomiting or have diarrhea and are unable to take their medicine orally should be given their medication through an IV (needle). If blood pressure, blood sugar, or electrolytes become abnormal, the child should be put in the hospital for careful monitoring and treatment. Talk to your doctor about signs to watch for and an action plan if your child becomes sick.

Antley-Bixler syndrome has a broad spectrum of health problems associated with it, and these can range from mild to severe. Common symptoms include premature closure of skull bones (craniosynostosis), flattened midface (midface hypoplasia), nasal passage blockage (choanal atresia), prominent forehead (frontal bossing), protruding eyes (proptosis) and low set, dysplastic ears. Other distinct features include multiple joint contractures, fusion of forearm bones (synostosis), unusually long, slender fingers (arachnodactyly), and bowing of the thighbones. Genital anomalies with sexual ambiguity due to impaired steroidogenesis can occur in a specific type of ABS. Intellectual development is variable.

To learn more about symptoms, please visit the "Symptoms" section.

Find a genetic counselor in your area for more information on hereditary conditions.
https://www.nsgc.org/page/find-a-genetic-counselor

The main symptoms of Antley-Bixler syndrome (ABS) are distinct skeletal abnormalities, particularly the head and facial area, with or without the presence of ambiguous genitalia. The abnormalities include premature closure of skull bones (craniosynostosis), flattened midface (midface hypoplasia), nasal passage blockage (choanal atresia), prominent forehead (frontal bossing), protruding eyes (proptosis) and low set, dysplastic ears. Other distinct features include multiple joint contractures, fusion of forearm bones (synostosis), unusually long, slender fingers (arachnodactyly), and bowing of the thighbones. Individuals with ABS commonly have heart and kidney malformations. Intellectual development is variable.

After a diagnosis of Antley-Bixler syndrome (ABS) is made, an evaluation is recommended to determine the extent of disease and needs of the individual. Referral to appropriate specialist for evaluation include endocrinology, clinical genetics, neurosurgery, otolaryngology, and cardiology. Functional adrenal studies, regardless of the presence of genital abnormalities, are recommended to assess steroid hormone deficiencies. Additional test to assess the extent of the disease include cranial CT scan and/or MRI, assessment for upper-airway obstruction, radiographs, echocardiogram, and abdominal and pelvic ultrasound.

Discuss with your doctor about any concerns you have or for a referral to a medical geneticist and other medical specialist. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website.

Find a Genetic Counselor in North America from the National Society of Genetic Counselors to discuss more.

Newborn screening does not currently test for Antley-Bixler syndrome (ABS). However, some cases are detected through a positive newborn screening for congenital adrenal hyperplasia. All newborns in the United States are screened for 21-hydroxylase deficiency, known as classic congenital hyperplasia. ABS with genital anomalies and disordered steroidogenesis is caused by a mutation in the POR gene. Disruptions to the POR gene reduces the activity of an enzyme required for steroid hormone production, cytochrome P450 oxidoreductase. Consequently, this disorder presents with a deficiency of 21-hydroxylase. Newborn screening does not appear to be sensitive enough to detect all individuals with ABS with genital anomalies and disordered steroidogenesis.

If you are concerned that your newborn may have this disorder, talk to your child’s pediatrician to about testing or further workup.

Antley-Bixler syndrome (ABS) without genital anomalies and disordered steroidogenesis is confirmed though molecule genetic testing. ABS without genital anomalies and disordered steroidogenesis is caused by a mutation in the FGFR2 gene, but similar presentations are found with mutations in FGFR1 and FGFR3. Therefore, molecular genetic testing of FGFR1, FGFR2, and FGFR3 may be helpful when diagnosis is unclear or questionable.

Discuss with your doctor about any concerns you have or for a referral to a medical geneticist, genetic counselor, and other medical specialist.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

Antley-Bixler syndrome (ABS) with genital anomalies and disordered steroidogenesis can be detected through biochemical and molecular genetic testing.

Biochemical Testing
ABS with genital anomalies and disordered steroidogenesis disrupts enzymatic function within the cholesterol and steroid synthesis pathways. Therefore, individuals with this type of ABS will have characteristic abnormalities of both sterol and steroid metabolism. These biochemical levels can be tested through blood and urine samples.

Molecular Genetic Testing
Molecular testing can confirm the diagnosis and differentiate between the two types of ABS. There are three genetic testing approaches:

Current clinical research can be found at https://clinicaltrials.gov/ . To learn more about the study of interest, such as eligibility criteria, you or your doctor can contact the study research staff provided on the website.

When the father is of older age (advanced paternal age), there is a higher risk to have a child with a de novo (brand new) mutation in the FGFR2 gene associated with Antley-Bixler syndrome without genital anomalies and disordered steroidogenesis. This mutation is not inherited from a parent, but occurs as a new mutation in the sperm that creates the baby.

Additionally, there is an increased risk to have a child with ABS with genital anomalies and disordered steroidogenesis when both parents are carriers of a POR mutation.

Antley-Bixler syndrome (ABS) without genital anomalies and disordered steroidogenesis is considered a FGFR-related craniosyntosis syndrome. Children with these syndromes benefit from a multidisciplinary team approach practiced at most craniofacial clinics. The team can identify and address physical, development, and psychosocial issues. Furthermore, craniosyntosis corrective surgery must be performed before 18 month old. It is common for repeat surgeries to be required.

Discuss with your doctor about any concerns you have or for a referral to a medical geneticist and other medical specialist.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website.

Treatments for Antley-Bixler syndrome (ABS) with genital anomalies and disordered steroidogenesis include steroid hormone replacement therapy, multiple surgeries, air management, and physical and occupational therapy for individuals with joint contractures and elbow synostosis. Functional adrenal studies, regardless of the presence of genital abnormalities, are recommended to assess steroid hormone deficiencies. Genital abnormalities such as hypospadias and cryptorchidism in males, and clitoromegaly and vaginal hypoplasia in females can be corrected through surgery. Craniosynostosis will also need surgical correction, with earlier surgical correction associated with a better cognitive outcome. A major concern individuals with ABS is airway obstructions. It is common to require an endotracheal intubation immediately after birth. Nasal stints or tracheotomy also may be required,

Discuss with your doctor about any concerns you have or for a referral to a medical geneticist and other medical specialist.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website.

There is no cure for Antley-Bixler syndrome. Treatment is limited to management and surveillance of medical concerns, and surgical intervention. For example, if someone has hydrocephalus, pressure inside the skull (intracranial pressure) may increase and a tube (shunt) may need to be surgically placed to drain the extra fluid from the brain. Infants who have premature fusion of many skull bones (craniosynostosis) and a severe skull deformity may need surgery early in the first year of life. There are published guidelines for management and surveillance for Crouzon syndrome on the website http://genereviews.org/.

People with Antley-Bixler syndrome are affected differently and it is difficult to predict the severity of medical concerns at birth. Some people are more mildly affected and some people are more severely affected. Not all people affected with Antley-Bixler syndrome in the same family are affected similarly.

When Antley-Bixler syndrome is caused by changes to the POR gene it is considered a disorder of steroidogenesis. Changes to the POR gene decreases activity of the cytochrome P450 oxidoreductase leading to the disruption of steroid hormone production.

Antley-Bixler syndrome (ABS) has a broad range of symptoms in which many can be corrected through proper clinical management. Skeletal abnormalities may be corrected surgically within the first couple months after birth. These surgeries can reduce the risk of secondary complications such as hydrocephalus (too much cerebrospinal fluid in the brain) and cognitive impairment.

Individuals who have ABS with genital anomalies and disordered steroidogenesis will need hormone replacement therapy to alleviate symptoms caused by cortisol deficiency. These therapies include testosterone or estrogen replacement males or females, respectively.

If you have ABS syndrome, your primary care provider should know the management and surveillance guidelines. Referrals to necessary specialists are typically needed early on, depending on the clinical features of the affected person. Some babies with ABS syndrome may have difficulty breathing through their nose and a breathing tube may be needed immediately after birth. A baby diagnosed with ABS syndrome should be seen by a plastic surgeon early on to discuss surgical correction of craniosynostosis.

For patients with Antley-Bixler syndrome (ABS) with genital anomalies and disordered steroidogenesis, during periods of illness or stress your body will need more corticosteroids than you generally take. Work with your endocrinologist to decide how much extra you should take and for how long you should take the extra medication.

If one parent Antley-Bixler Syndrome (ABS) without genital anomalies and disordered steroidogenesis, there is a 50% chance that any of their children will also have this condition. Because our genes come in pairs, there is a 50% chance the affected parent will pass on their "non-working" gene and a 50% chance they will pass on there "working" gene to their offspring.
A genetic counselor can help you learn more. Genetic counselors can be found on the National Society of Genetic Counselors website.

All children of an individual with Antley-Bixler syndrome (ABS) with genital anomalies and disordered steroidogenesis will be obligated carriers. This mean the children will have one pathogenic variant in the POR gene. However, reproduction in individuals with this type of ABS have not been reported.

Find a Genetic Counselor in North America from the National Society of Genetic Counselors to discuss more.

Fertility may be a concern for individuals with Antley-Bixler syndrome (ABS) with genital anomalies and disordered steroidogenesis. However, there is a lack of reports describing reproduction in individuals who have ABS with genital anomalies and disordered steroidogenesis, and therefore, the prevalence of reproduction is uncertain.

If the disease-causing variant has been identified in an affect family, babies can be diagnosed before birth with genetic testing through chorionic villus sampling or amniocentesis. Chorionic villus sampling is a procedure that is done between 11 and 14 weeks of pregnancy. A catheter is put through the cervix, and a small piece of the developing placenta is taken for genetic testing. It has been associated with up to a 1% risk of miscarriage. Amniocentesis is done at 15 weeks of pregnancy or later. It involves putting a needle in to the amniotic sac and removing fluid for genetic testing. It has been associated with up to a 1 in 300 risk of miscarriage, but newer studies suggest that the risk is likely much lower. To learn more about testing options, find a genetic counselor near you on the National Society of Genetic Counselors’ website.

Depending on the type of Antley-Bixler syndrome (ABS), it can be inherited in an autosomal dominant or autosomal recessive manner. An autosomal dominant condition occurs when a change to one copy of a gene is enough to cause the condition. Genes are found in cells and contain instructions that allow the body to function normally. They exist in pairs because one copy is inherited from the mother and the other copy from the father. An autosomal recessive condition occurs when changes to both gene copies cause the condition. This means that people with one altered gene do not develop the condition and typically do not have any symptoms. They are said to be carriers of the condition.

ABS has two inheritance patterns because the two types of ABS have different genetic causes. ABS without genital anomalies and disordered steroidogenesis is caused by a change to the FGFR2 gene and is autosomal dominant. Therefore, a change to one copy of the FGFR2 gene is enough to cause ABS. This type of ABS may be inherited from an affected parent or may be the result of a new change in that individual. Each child of an affected parent would have a 50% chance to inherit the altered copy of FGFR2 and thus be affected with ABS. ABS with genital anomalies and disordered steroidogenesis is due to changes in the POR gene and is autosomal recessive. Parents of an individual with this type of ABS are obligated carriers for the condition. If parents have one affected child, they are at 25% risk to have another affected child.

A genetic counselor can help you understand more about how ABS is inherited in your family. Genetic counselors can be found on the National Society of Genetic Counselors website.

The presence of craniosynostosis (premature closure of skull bones) and radiohumeral synostosis (fusion of adjacent arm bones) at birth are the minimum criteria for a diagnosis of Antley-Bixler syndrome. Molecular genetic testing is desirable to confirm the diagnosis and to differentiate between the two types of ABS: ABS with genital anomalies and disordered steroidogenesis, and ABS without genital anomalies and disordered steroidogenesis.

Discuss with your doctor about any concerns you have or for a referral to a medical geneticist and other medical specialist.

To discuss arranging genetic testing for Antley-Bixler syndrome, contact a local genetic counselor. Genetic counselors can be found on the National Society of Genetic Counselors website.

There are multiple sites where you can donate to organizations doing research in skeletal abnormalities and human development:

The presence of craniosynostosis (premature closure of skull bones) and radiohumeral synostosis (fusion of adjacent arm bones) at birth are the minimum criteria for a diagnosis of ABS. However, it is also important to distinguish between the two types of ABS due to the difference in inheritance patterns and the vulnerability to different risk factors. The two types can be distinguished through clinical findings of ambiguous genitalia, or a biochemical blood test checking for steroid abnormalities. Molecular genetic testing is desirable to confirm a diagnosis of ABS and which type is, especially when physical and laboratory findings are inconclusive.

Discuss with your doctor about any concerns you have or for a referral to a medical geneticist and other medical specialist.

To discuss arranging genetic testing for Antley-Bixler syndrome, contact a local genetic counselor. Genetic counselors can be found on the National Society of Genetic Counselors website.

Clinical research can be found on the following sites:

Consult with your doctor or a genetic counselor to find specialists in your area. Find a Genetic Counselor in North America from the National Society of Genetic Counselors to discuss more. A list of craniofacial clinics can be found here: http://www.faces-cranio.org/MedCent.htm

Antley-Bixler syndrome (ABS) is a very rare genetic disorder, however it is suspected that many mild cases have not been reported. Currently, the prevalence of ABS is unknown.

Everyone with Antley-Bixler syndrome has a gene mutation in either the FGFR2 gene or the POR gene.

There have been 5 reported cases of ABS-like features due to early prenatal exposure to oral, high-dose fluconazole. However, only a few select symptoms were seen in these babies.

A genetic counselor can help you learn more. Genetic counselors can be found on the National Society of Genetic Counselors website.

Antley-Bixler syndrome appears to affect males and female equally.

Intellectual disability is a minor concern for individuals with Antley-Bixler syndrome. The degree of cognitive impairment is likely associated with the severity of craniosyntosis (premature fusion of many skull bones) and timing of corrective surgery.

Testing is available Antley-Bixler syndrome (ABS) even before pregnancy. This testing is called preimplantation genetic diagnosis, or PGD. PGD involves in vitro fertilization (IVF). The embryos that come from the IVF can be tested for ABS. Only the embryos found not to have the condition are used for a pregnancy. It will be very important for you to have genetic testing for ABS before starting the IVF process. To learn more about PGD and your reproductive options, find a genetic counselor at the National Society of Genetic Counselors’ website. You will also need to work with a reproductive endocrinologist who does PGD with IVF. Speak to your doctor about a referral to a reproductive endocrinologist in your area.

Antley-Bixler syndrome (ABS) can be referred to by many names. The list below separates the two forms of ABS and their associated alternative names.

ABS with genital anomalies and disordered steroidogenesis

There are many support groups for craniofacial differences, such as:

There are two types of Antley-Bixler syndrome (ABS): ABS with genital anomalies and disordered steroidogenesis, and ABS without genital anomalies and disordered steroidogenesis. They are two distinct disorders caused by mutations in the POR gene or the FGFR2 gene, respectively. As the name suggests the difference between the two types is the presence or absence of genital abnormalities and disordered steroidogenesis. Treatment for ABS – POR related form would include hormone replacement therapy to correct the deficiency in steroid hormone production. Life expectancy for both types are dependent on the severity of the skeletal malformations.

Discuss with your doctor about a referral to a medical geneticist if the type of ABS is unclear.
A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website.

There are many disorders with the primary feature of premature closure of skull bones (craniosynostosis). Antley-Bixler syndrome (ABS) needs to be distinguished from Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2 related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), Saethre-Chotzen syndrome, Boston-type craniosynostosis, Shprintzen-Goldberg syndrome and Muenke syndrome.
Antley-Bixler syndrome also looks a lot like congenital adrenal hyperplasia (CAH). CAH is a group of conditions that are characterized by impaired synthesis of steroid hormones. It would present with genital abnormalities similar to ABS type with genital anomalies and disordered steroidogenesis.

Discuss with your doctor for referral to a medical geneticist to determine the correct diagnosis.

A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website.