Introduction

Catel-Manzke Syndrome (often shortened to CMS) is a very rare genetic condition that babies are born with.¹ This condition displays two main symptoms: Pierre Robin sequence (PRS),² which includes a tiny lower jaw that can lead to further complications, and hyperphalangy with radial deviation of the index finger (the index finger is bent towards the thumb due to an extra small bone in the finger)¹. Babies with this syndrome often have difficulty breathing and feeding.

This syndrome shares overlapping features with various skeletal dysplasias due to its mutation in the TDP-glucose 4,6-dehydratase (TGDS) gene (which plays a role in nucleotide sugar metabolism), making it challenging to diagnose successfully.³ Inaccurate diagnosis can delay appropriate breathing and feeding management, lead to inaccurate genetic counselling, introduce unnecessary testing and monitoring for complications not associated with CMS, and give parents wrong expectations of the future.⁴

This article aims to explain in simple terms what CMS looks like, how it compares to other conditions, and why getting the name right is crucial to support more accurate clinical evaluations.

Section I: What catel-manzke syndrome looks like 

CMS was first described by Catel in 1961 and later detailed by Manzke in 1975. Signs of CMS are shown very early in children. Main features of CMS include:

• Pierre Robin Sequence: This condition is characterised by a small chin (micrognathia), a tongue that slides backwards (glossoptosis), and a cleft palate is often present. This can cause difficulties with breathing and feeding, and sometimes surgery or special feeding or breathing support may be necessary²
• Manzke dysostosis: An extra small bone in the index finger (hyperphalangy) causes it to bend and point towards the thumb noticeably (radial deviation)⁵

Other features include failure to thrive in babies, congenital heart defects, joint hypermobility or chest shape differences. These features are inconsistent and should not be used as diagnostic markers; however, they should be taken into consideration.⁶

Genetic factor: CMS inheritance pattern is biallelic autosomal recessive, meaning that both parents must each carry at least one copy of the mutated gene (TGDS) for the child to have the condition.³ The TGDS (TDP-glucose 4,6-dehydratase) gene provides instructions for producing an enzyme that functions as a repair enzyme for a sugar chain essential in the formation of cartilage and bones.³ Parents themselves usually do not have the condition, but there is a 25% chance that the child will have it if they are both carriers.

Interestingly, more recent reports show that not all children with CMS have the “classic” hyperphalangy. Without the extra bone, some people might be small in stature or have a slight finger bend. Showing that CMS appears differently from child to child, and diagnosis should be a combination of X-rays, genetic testing, and clinical evaluation.⁷

Section II: Other conditions that can be confused with CMS 

CMS is frequently mistaken for other, more well-known conditions. Disorders such as Stickler syndrome, Treacher Collins syndrome, Nager syndrome, and others can closely resemble CMS in infancy, making accurate diagnosis difficult without specialised evaluation. 

Some differentials for CMS include:

• Stickler syndrome is a connective tissue disorder caused by mutations in collagen genes. Like CMS, Stickler syndrome shows symptoms of  Pierre-Robin sequence - a small jaw, breathing problems, and a cleft palate. At first glance, this seems almost identical to CMS. However, Stickler has its own tell-tale signs, such as progressive myopia (severe near-sightedness), retinal detachment, hearing loss, joint hypermobility and joint pain as they grow. Unlike Catel-Manzke syndrome (CMS), there is no finger abnormality in Stickler syndrome⁸
• Nager syndrome, also known as acrofacial dysostosis, can involve features such as a small jaw and cleft palate, similar to CMS at first glance. In Nager syndrome, skeletal changes involve radial ray defects, such as hypoplastic thumbs (small or absent thumb bones), radioulnar synostosis (a fusion between the radius and ulnar bones in the forearm), and shortened forearms. Unlike CMS, bone abnormalities in Nager affect the thumb and forearm rather than the index finger. The genes affected in Nager (SF3B4) also differ from those in CMS^9,10  
• Treacher Collins syndrome (TCS), also known as mandibulofacial dysostosis, is another disorder that overlaps with CMS in terms of jaw and palate features. Yet, TCS is also distinctly characterised by malar hypoplasia (underdeveloped cheekbones), downward-slanting eyes, lower eyelid colobomas (missing lower eyelid), and ears that are partly formed or missing. Unlike CMS, hands and fingers are unaffected in TCS. Genetically, TCS results from mutations in TCOF1, POLR1C, or POLR1D, which disrupt ribosomal biogenesis¹¹
• Cornelia de Lange syndrome (CdLS) is another condition that resembles CMS due to the presence of small jaw and palate dysfunctions; however, the differences are even more striking. Children with CdLS often have a distinctive facial appearance, characterised by joined arched eyebrows, long eyelashes, and an upturned nose. They also often have severe developmental delays, differences in limb development and behavioural challenges. These broader and more systemic issues set CdLS apart from CMS¹²

Beyond these well-known conditions, doctors also consider rarer syndromes that can resemble CMS. Desbuquois syndrome may cause an extra bone in the index finger, like CMS, but is paired with more severe skeletal growth problems and joint looseness.¹³ Larsen syndrome is recognised for its multiple joint dislocations at birth, which go far beyond the localised finger changes of CMS.³ While some finger and facial characteristics of temtamy preaxial brachydactyly syndrome (TPBS) can be similar to those of CMS, the characteristic combination of PRS and bent index finger is absent.³ This shows how small overlaps can hide very different underlying conditions.  

It is worth noting that Pierre Robin Sequence can present in isolation without involvement of other systems. There are, however, other conditions that involve PRS but are distinct from CMS due to the involvement of different systems. Additional problems help separate these disorders from CMS; for example, conditions such as,¹⁴ which also present with heart defects, a weak immune system and low calcium levels, or CHARGE syndrome, which manifests as issues with the heart, breathing, vision, and hearing.¹⁵

Section III: How doctors tell the difference 

Doctors don’t rely on one clue alone – they put the puzzle together. A structured diagnostic approach is essential when evaluating for CMS.

• Clinical Examination: The doctor performs a thorough physical examination, assessing the face for craniofacial structures (such as a small jaw), the mouth for palate integrity (cleft palate), and the hands for digital morphology (looking for a bent index finger)¹
• Radiographic imaging: Plain X-rays of the hands can show a tiny extra bone in the index finger and any duplication or splitting of the proximal phalanx bone. This is something that is rarely seen in conditions other than CMS. It is important to note that the absence of this feature does not exclude CMS⁵
• Genetic testing: A blood test can check for genetic changes. Targeted sequencing of the TGDS gene should be performed when CMS is suspected. Whole-exome sequencing would be essential to exclude other similar conditions, such as Stickler, Nager, and TCS⁷
• Family History: A thorough understanding of family history is crucial for the successful diagnosis of CMS. CMS is an autosomal recessive condition, meaning it often appears in families where both parents are carriers, even though they appear completely healthy. Other conditions, such as Stickler syndrome and Treacher Collins syndrome, are usually autosomal dominant^2,11,16
• Emerging Biochemical Clues: By inhibiting the encoding of an enzyme essential to the glycan synthesis pathway, TGDS deficiency causes abnormalities in skeletal development. According to research, this connects CMS to a larger class of metabolic skeletal dysplasias^3,6
• Multidisciplinary Assessment: Working as a team with input from paediatricians, geneticists, orthopaedists, ENT specialists, and speech therapists is essential to accurately diagnosing CMS⁶

Section IV: Why getting the right diagnosis matters 

Correctly identifying CMS rather than similar disorders has significant clinical implications.

• Treatment planning: Children with breathing and feeding difficulties require the most appropriate type of support, which may include surgery to enlarge the jaw and improve breathing, special positioning, feeding tubes to enhance feeding, or surgery or therapy to improve hand function when finger differences may benefit from these interventions¹
• Avoiding unnecessary tests/surveillance: Misdiagnoses of CMS can lead to regular, unnecessary tests. For example, if CMS is diagnosed as Stickler, a child might undergo multiple repeated eye exams for surveillance of problems that would never develop¹
• Family planning/genetic counselling: a correct diagnosis could advise families regarding recurrence. CMS is recessive; therefore, there is a 25% chance in each pregnancy if both parents are carriers, compared to dominant conditions like Treacher Collins³
• Expectations for the future: An accurate diagnosis can help parents prepare for the future without worrying about unrelated problems associated with other conditions, such as severe ear anomalies in Treacher Collins syndrome or vision loss in Stickler syndrome. Knowing the correct condition can provide more precise explanations and peace of mind^11,16

Summary

Catel-Manzke Syndrome (CMS) is a rare genetic condition characterised by Pierre Robin sequence (small jaw, cleft palate, and breathing difficulties) and a bent index finger caused by an extra small bone. Because many other disorders—such as Stickler, Nager, Treacher Collins, Cornelia de Lange, DiGeorge, and CHARGE syndromes—share overlapping features, CMS is often difficult to diagnose accurately. CMS-specific characteristics include specific finger changes in the index finger, its inheritance pattern through TGDS gene mutations, and the absence of many broader complications seen in other conditions. Identifying these differences ensures that children receive the most appropriate care, avoid unnecessary testing, and provide families with accurate genetic counselling and realistic expectations for the future.