Introduction
Catel Manzke Syndrome (CMS) is a very rare genetic condition. A genetic condition means that it is inherited from your biological parents. Catel Manzke was originally called palato digital syndrome. This means there is a difference in the appearance of the index finger on the hands. People with CMS have an extra bone in their index finger, compared to the general population. The condition was researched initially in the 1960s. However, there is a lack of research studies due to the small number of people who are affected by this condition. There is also Clinodactyly of the 5th finger (smallest finger), which means that this finger bends towards the 4th finger.1
Understanding catel manzke syndrome
Causes and genetics of CMS
CMS is an autosomal recessive disorder. This means that both parents need to have an affected phenotype for the child to be affected by the disorder. Each parent has two copies (alleles). Both parents need to have the pathogenic allele for the child to show symptoms of the disorder. However, if only one parent has an affected allele, then the child will be a carrier for the disorder, which means they can pass on the allele to their children but would not show any symptoms themselves.1
Pierre Robin sequence refers to a group of symptoms that are seen in individuals with CMS. One of the main differences for people with CMS is a U-shaped cleft palate (roof of your mouth).
Polyhydramnios
This is a condition in which there is an increased amount of amniotic fluid surrounding the baby. In babies with CMS, it is common for the birthing parent to have polyhydramnios.3
Short stature is observed in patients with CMS.5
Prevalence of CMS
41 cases of CMS have been documented in scientific journals since the first case was reported in the 1960’s. This makes CMS a very rare condition, and as such, there is still a small amount of research into this disease compared to other genetic conditions.5
Key clinical features and symptoms
Craniofacial differences
One of the main craniofacial differences in CMS is glossoptosis.
This is a condition associated with CMS in which the tongue is placed further back in the mouth towards the tonsils. This can cause obstruction to the airway.2
- Congenital heart defects
Ventricular or atrial septal defects. This is usually called a hole in the heart and can be diagnosed at birth or found later as an incidental finding when an electrocardiogram is completed (for a different reason).7
Ocular hypertelorism is the name for when there is a greater distance between the eyes than in the general population. Individuals also tend to have larger cheeks.8
Other key clinical features of CMS include:
- Absent, partially missing or shortened fingers and toes
- Abnormalities to the jaw, such as micrognathia, retrognathia, or a partially missing mandible
- U-shaped cleft palate
- Smaller than average mouth and hypoglossal
- Abnormalities to the limbs
- Missing major salivary glands and teeth.6
Related conditions
Desbuquois dysplasia type 1 is a condition which shares a number of clinical features with CMS. Some of the main similarities are in hand abnormalities and short stature.
Diagnosis and screening
c.298G > T (p.Ala100Ser) is one of the main pathogenic variants (disease-causing mutation) associated with CMS. Sequencing of the DNA is required to determine if the patient has a pathogenic variant, and this is usually completed with Sanger of Next Generation Sequencing. In this method, the entire gene or region of the DNA is sequenced and then compared against a known positive control. In the above variant, you can see that a G has been changed to a T at place 298. This changes the alanine amino acid to a serine amino acid at place number 100.4
TGDS is a gene that encodes for the enzyme TDP-Glucose 4,6-Dehydratase. It is not known yet how mutations in this gene cause CMS. It’s possible that in patients with CMS, there is a problem with proteoglycan metabolism. Proteoglycans provide structure to our cells. TDP-glucose 4,6-dehydratase is also associated with metabolising retinoids, hormones (steroid-based like testosterone), lipids and xenobiotics.10 Examples of xenobiotics are food additives and environmental pollutants. (4)13q32.1 is the location of the TGDS. This means that the TGDS locus is on chromosome 13. Each chromosome has a long and short arm, and this gene is located on the long arm.
Further research on other genetic links
There has also been research into other genes and how they may impact people with CMS. Mutations in the gene KYNU have also been researched as a potential cause of CMS. This is a gene that codes for the enzyme kynureninase.4 CANT1 and IMPAD1 are two other genes that have been researched in cases of people with CMS. CANT1 mutations were not found in any of the five individuals that were tested. However, two individuals had a mutation in the IMPAD1 gene. One individual was homozygous for the mutation c.559C>T (p.Arg187X). This is a type of nonsense mutation. The other individual had a homozygous mutation at point c.324del (p.Ser108ArgfsX48). This is a frameshift mutation that results in a stop codon being introduced into the protein-coding sequence. This is a mutation that will cause a greater effect on the overall protein.11
Genetic testing and counseling
Genetic testing for CMS can be carried out on prospective parents who may show some of the clinical features of CMS, for example, if they present with an extra bone in their index finger. Sometimes, people who do not show symptoms may have genetic testing if the couple are having repeat pregnancy loss. This would be part of a larger panel of testing.
Importance of early diagnosis
An early diagnosis is essential in order to implement strategies to reduce the impact of craniofacial differences. Congenital heart defects that are not found promptly may cause problems for the individual later on. One of the main reasons for prompt diagnosis is to help with feeding and maintaining an airway in newborns. Due to the rarity of the condition, emphasis is put on treating each individual component so that the individual can thrive and gain weight.
Treatment and management
A multidisciplinary approach is required for the treatment and management of CMS. Clinicians and surgeons will perform surgeries and interventions to manage the symptoms of CMS. Pathologists and geneticists will look at genetic mutations within the patient’s DNA and also examine any blood or other bodily fluids provided to aid in diagnosis. Physiotherapists and occupational therapists will help individuals with adaptations in their everyday lives. For example, help with feeding if craniofacial abnormalities cause issues with being able to eat or drink effectively.
Living with catel manzke syndrome
Challenges faced by individuals with CMS will initially involve problems with feeding due to the presence of a cleft palate. A hole in the roof of the mouth may make breastfeeding and bottle feeding harder. Infections may also be a concern if food enters the hole in the roof of the mouth. Congenital heart defects may also be present, which will require corrective surgery. Coping strategies and support networks are available for patients with rare genetic conditions. The severity of the individual’s condition will determine the level of care that they require from occupational therapists and other clinicians. Rare disease support groups campaign for better access to genetic testing for newborns and also act as a support for parents and individuals associated with rare diseases like CMS.
Research
It is possible that new pathogenic variants that present with the same cluster of clinical features such as CMS will be found. Each variant will be documented in scientific literature so that a bigger picture can be gathered on the genetic causes of CMS.
Sanger sequencing from peripheral blood monocytes can give an accurate answer as to whether a patient has the pathogenic variant. Sequencing techniques are getting quicker and cheaper to run, making the process available to more people than ever before. There is also work on the Human Genome Project to improve understanding of DNA sequences of various rare genetic disorders so that we can better aid personalised medicine in the future.1
Conclusion
CMS is a very rare condition which has numerous clinical features that have been reported. There is a known genetic mutation that causes the syndrome, which makes it easier to diagnose the condition in others. Symptoms are present from birth, and as such, the condition is usually diagnosed in newborn infants. It is important to raise awareness of CMS and support families and individuals that are affected. With advances in reconstructive surgeries and surgery to fix cardiac abnormalities, people with CMS have a bright future.
References:
- Pferdehirt R, Jain M, Blazo MA, Lee B, Burrage LC. Catel-Manzke Syndrome: Further Delineation of the Phenotype Associated with Pathogenic Variants in TGDS. Mol Genet Metab Rep. 2015;4:89-91. doi:10.1016/j.ymgmr.2015.08.003
- Schweiger C, Manica D, Kuhl G. Glossoptosis. Semin Pediatr Surg. 2016;25(3):123-127. doi:10.1053/j.sempedsurg.2016.02.002
- Brewer FR, Harper LM. 137 - Pierre Robin Sequence. In: Copel JA, D’Alton ME, Feltovich H, Gratacós E, Krakow D, Odibo AO, et al., editors. Obstetric Imaging: Fetal Diagnosis and Care (Second Edition) [Internet]. Second Edition. Elsevier; 2018. p. 570-572.e1. Available from: https://www.sciencedirect.com/science/article/pii/B9780323445481001376
- Ehmke N, Caliebe A, Koenig R, Kant SG, Stark Z, Cormier-Daire V, et al. Homozygous and Compound-Heterozygous Mutations in TGDS Cause Catel-Manzke Syndrome. The American Journal of Human Genetics. 2014;95(6):763–70.
- Miller DE, Chow P, Gallagher ER, Perkins JA, Wenger TL. Catel–Manzke syndrome without Manzke dysostosis. American Journal of Medical Genetics Part A. 2020;182(3):437–40.
- Gewitz M, Dinwiddie R, Yuille T, Hill F, Carter CO. Cleft palate and accessory metacarpal of index finger syndrome: possible familial occurrence. Journal of Medical Genetics. 1978 Apr 1;15(2):162–4.
- Schoner K, Bald R, Horn D, Rehder H, Kornak U, Ehmke N. Mutations in TGDS associated with additional malformations of the middle fingers and halluces: Atypical Catel-Manzke syndrome in a fetus. Am J Med Genet A. 2017;173(6):1694-1697. doi:10.1002/ajmg.a.38209
- Sharma RK. Hypertelorism. Indian J Plast Surg. 2014;47(3):284-292. doi:10.4103/0970-0358.146572
- Boschann F, Stuurman KE, Bruin C, Slegtenhorst M, Duyvenvoorde HA, Kant SG, et al. TGDS pathogenic variants cause Catel‐Manzke syndrome without hyperphalangy. Am J Med Genet. 2020 Mar;182(3):431–6.
- Patterson AD, Gonzalez FJ, Idle JR. Xenobiotic metabolism: a view through the metabolometer. Chem Res Toxicol. 2010;23(5):851-860. doi:10.1021/tx100020p
- Nizon M, Alanay Y, Tuysuz B, Kiper POS, Geneviève D, Sillence D, et al. IMPAD1 mutations in two Catel-Manzke like patients. Am J Med Genet. 2012 Sep;158A(9):2183–7.
