The syndrome was first described in 1974 by Alasdair Hunter and his peers at the Montreal Children's Hospital.[4] It was not until 1989 that it was labelled COACH syndrome, by Verloes and Lambotte, at the Sart Tilman University Hospital, Belgium.[5]
Signs and symptoms
An example of coloboma of the eye
Signs of COACH syndrome tend to present from birth to early childhood. Facial abnormalities are a common symptom, with some characteristics being broadness of the forehead, ptosis of either one or both eyes and misalignment of the eyes.[6] Other cases also report a "carp" shaped mouth, flattened face and nose and hypertelorism.[5]
Patients are often within the lower percentiles for height and weight growth.[3]Hypotonia is a possible sign of COACH syndrome.[3] Infants with COACH syndrome may experience very categorical hyperventilation and complications with respiration, such as irregular breathing. It has been reported that as patients surpass infancy, these respiratory issues may disappear.[7]
Behavioral and intellectual delays are symptoms caused by the hypoplasia of the cerebellar vermis and oligophrenia.[8][9] This implies delayed onset of speech and walking, along with learning and social issues.[4] Poor motor skills and balance, speech impairment, mild gait or hand ataxia and irregular eye movement are symptoms of the disease attributed to congential ataxia.[10]
Coloboma of the eye is visible in the retina as "hole" in its structure, and causes low vision, possible sensitivity to light and variance in size of the eyeball.[11][12] The build-up of tissue in the liver, known as hepatic fibrosis, may cause symptoms such as jaundice, ascites, abnormal bleeding and enlarged spleen.[12] Kidney complications in the form of polycystic kidney or nephronophthisis is estimated to affect 77% of patients with COACH syndrome, and is therefore a highly significant symptom of the disease.[6]
Genetics
A diagram of the structure of a primary cilium
Due to generational familial linkage and the frequency of siblings sharing inheritance of COACH syndrome, it is classified as an autosomal recessive disorder. COACH syndrome is a ciliopathy, a group of diseases categorized by irregular behavior of the primary cilia, which are involved in cell division, transportation, communication and tissue differentiation. This leads to irregular tissue growth in organs and various other diseases.[6] 83% of COACH syndrome carriers presented with either one or two mutations on the MKS3 gene, and findings suggest this is where most of the symptoms can be accredited. CC2D2A and RPGRIP1L genes may also have some minor contributions, with around 8.7% reporting a mutation on the CC2D2A gene and 4.3% on the RPGRIP1L gene. These three genetic mutations reportedly cover 96% of families with COACH syndrome.[13]
Detection of the hypoplasia of the cerebellar vermis is achieved through a cranial magnetic resonance imaging (MRI) scan. The presence of the 'molar tooth sign' (MTS) on the MRI scan, a mid- brain hind- brain malformation, confirms this condition and is a key indicator of COACH syndrome. The MTS's distinguished shape is attributed to the lengthened superior cerebellar peduncles and deepened interpeduncular fossa.[6] To diagnose ataxia, both neurological assessment and physical examination are required. This can include MRI scans, study of behavior and motor skills in infancy and analysis of family history and genetics. In the case of congenital ataxia, patients are born with the condition and thus diagnosis is more difficult, therefore diagnosis of ataxia alone is not sufficient to indicate COACH syndrome, and must be used in conjunction with other symptoms.[10] Oligophrenia, more commonly known as intellectual disability, is diagnosed using personalized testing to measure intelligence and physical examination for anomalies and facial dysmorphia.[14]Hepatic fibrosis has a range of diagnostic techniques, including invasive and non- invasive. Liver biopsy examination is an invasive technique, which uses liver tissue extracted from the patient to identify the degree and severity of the fibrosis, and may also provide insight on tumor growth. Ultrasonography- based tests use radiation waves to measure the stiffness of the tissue and are non- invasive. Serum tests are also non- invasive, and diagnose liver complications on the basis of the amount and presence of certain proteins and chemicals in the body.[15] Kidney cysts can be discovered using ultrasound techniques, and monitoring of the patient's urine concentrating ability for any abnormalities can indicate other renal complications such as nephronophthisis.[6][7]
Management
A diagram of dialysis treatment for renal complications
There is no cure for COACH, syndrome, therefore treatment targets the various complications it implies and management of the disease and its symptoms.
Management includes monitoring patients' neurological activity, development patterns and renal and hepatic function annually. Programs for special education and occupational therapy for speech and motor impairment can improve symptoms of intellectual disability and quality of life for patients. Families and patients are offered ongoing psychological support and specialized care is provided to aid societal integration. In some cases, antiepileptic drugs or neuroleptics are prescribed to reduce anger and behavioral difficulties and improve mood.[14] Some children with hypotonia and other motor skill complications may need a nasogastric feeding tube in order to ensure adequate nutrients are received and breathing is undisrupted.[6]
Ophthalmological surgery may be used to treat coloboma and ptosis of the eye to improve vision and appearance. A common technique to treat coloboma is intraocular lens (IOL) implantation, whereby a lens is surgically inserted and adhered to the iris to improve vision and appearance. In some severe cases, in conjunction with the IOL implantation, an artificial iris may be inserted into the lens capsule to treat this condition.[16] To treat ptosis, upper eyelid blepharoplasty is used for both cosmetic and functional reasons. Excess muscle and fat is removed, and the lid is raised in this procedure, and it is considered a minor procedure.[17]
If kidney function is abnormal, dialysis is a viable method of management, though is not a cure. Dialysis involves the refiltering of the blood through an external dialyzer, and is done usually three times a week to improve quality of life.[18] In most advanced cases, a kidney transplant will be required in order to ensure patient survival.[6]Hepatic fibrosis has a variety of treatment options, including anti-fibrotic methods, which aim to prevent the build-up of tissue in the liver. There are multiple methods, such as the targeting or clearance of collagen- generating cells, deactivation of receptors to certain cytokines and inhibition of connective tissue growth factor (CTGF). In cases of advanced fibrosis causing liver failure, liver transplant surgery is necessary to restore function.[13][15]
Prognosis
COACH syndrome is categorized as a Jobert syndrome related disorder (JSRD). Joubert syndrome affects approximately 1 in 80,000 to 1 in 100,000 live births, meaning it is a rare disease, while COACH syndrome is even more rare, with only 43 cases being reported from its discovery until 2010.[3] It is estimated to occur in less than one in one million people.[1] Due to this rarity, the prognosis of the disease is dealt with case- by- case. Survival depends on the severity of the symptoms, with most patients surviving infancy.[6] The likely causes of death with the progression of time are a renal and hepatic failure in later stages of life.[19]
History
The first official report of COACH syndrome was published in 1974 at the Montreal Children's Hospital, identifying two siblings, a brother and sister, presenting with all 5 components of the disorder. The report summarizes the family history and provides detailed case reports on the two siblings, analyzing all health abnormalities to reach a conclusion about the condition. The siblings both presented with the symptoms of congenital hepatic fibrosis, choroidal colobomata, dysmorphic features, polycystic kidneys, encephalopathy causing intellectual disability and growth problems. The report concludes that the symptoms presented by the siblings are not completely consistent with any other existing disorders, and thus prompted further research into the official classification of COACH syndrome in 1989.[4]
Summary of the Symptoms Present in 2 Siblings with COACH Syndrome in 1974
Symptom
Sibling 1
Sibling 2
Mastoiditis and sinusitis
Yes
Yes
Dermatolglypics
No
Yes
Extra finger
No
Yes
Low hairline
No
Yes
Ptosis of eyes
No
Yes
High palate
Yes
Yes
'Carp'- shaped mouth
Yes
Yes
Short middle 3 toes
Yes
No
Flat nose
No
Yes
Abnormal or underdeveloped ears
Yes
Yes
Anteverted nostrils
Yes
Yes
Perinatal complications
Yes
Yes
Pronounced forehead
Yes
Yes
Hypertelorism of eyes
Yes
Yes
Strabismus
Yes
Yes
Nystagmus
Yes
Yes
Decreased muscle
Yes
Yes
Slurred speech
Yes
No
Irregular movements
Yes
Yes
Ataxia
Yes
Yes
Intellectual deficit
Yes
Yes
Coloboma of the eye
Yes
Yes
Renal anomalities
Yes
Yes
Hepatic fibrosis
Yes
Yes
The official report classifying COACH syndrome in 1989 by Verloes and Lambotte assesses the disorder in two siblings and a third unrelated child, finding very similar symptoms to the initial report in 1974. The report concludes by suggesting that more cases of the disorder need to be reported in order to refine its definition, and assigns the name COACH syndrome as an acronym for the major symptoms.[5]
Related Research Articles
Joubert syndrome is a rare autosomal recessive genetic disorder that affects the cerebellum, an area of the brain that controls balance and coordination.
Caroli disease is a rare inherited disorder characterized by cystic dilatation of the bile ducts within the liver. There are two patterns of Caroli disease: focal or simple Caroli disease consists of abnormally widened bile ducts affecting an isolated portion of liver. The second form is more diffuse, and when associated with portal hypertension and congenital hepatic fibrosis, is often referred to as "Caroli syndrome". The underlying differences between the two types are not well understood. Caroli disease is also associated with liver failure and polycystic kidney disease. The disease affects about one in 1,000,000 people, with more reported cases of Caroli syndrome than of Caroli disease.
Cerebellar hypoplasia is characterized by reduced cerebellar volume, even though cerebellar shape is (near) normal. It consists of a heterogeneous group of disorders of cerebellar maldevelopment presenting as early-onset non–progressive congenital ataxia, hypotonia and motor learning disability.
Alagille syndrome (ALGS) is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 30,000 to 1 in every 40,000 live births. It is named after the French pediatrician Daniel Alagille, who first described the condition in 1969.
The cerebellar vermis is located in the medial, cortico-nuclear zone of the cerebellum, which is in the posterior fossa of the cranium. The primary fissure in the vermis curves ventrolaterally to the superior surface of the cerebellum, dividing it into anterior and posterior lobes. Functionally, the vermis is associated with bodily posture and locomotion. The vermis is included within the spinocerebellum and receives somatic sensory input from the head and proximal body parts via ascending spinal pathways.
Agenesis of the corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum. It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres in the brain, in the embryo is disrupted. The result of this is that the fibers that would otherwise form the corpus callosum are instead longitudinally oriented along the ipsilateral ventricular wall and form structures called Probst bundles.
Dandy–Walker malformation (DWM), also known as Dandy–Walker syndrome (DWS), is a rare congenital brain malformation in which the part joining the two hemispheres of the cerebellum does not fully form, and the fourth ventricle and space behind the cerebellum are enlarged with cerebrospinal fluid. Most of those affected develop hydrocephalus within the first year of life, which can present as increasing head size, vomiting, excessive sleepiness, irritability, downward deviation of the eyes and seizures. Other, less common symptoms are generally associated with comorbid genetic conditions and can include congenital heart defects, eye abnormalities, intellectual disability, congenital tumours, other brain defects such as agenesis of the corpus callosum, skeletal abnormalities, an occipital encephalocele or underdeveloped genitalia or kidneys. It is sometimes discovered in adolescents or adults due to mental health problems.
Papillorenal syndrome is an autosomal dominant genetic disorder marked by underdevelopment (hypoplasia) of the kidney and colobomas of the optic nerve.
3C syndrome is a rare condition whose symptoms include heart defects, cerebellar hypoplasia, and cranial dysmorphism. It was first described in the medical literature in 1987 by Ritscher and Schinzel, for whom the disorder is sometimes named.
Uner Tan syndrome (UTS) is a syndrome that was discovered by the Turkish evolutionary biologist Üner Tan. People affected by UTS walk with a quadrupedal locomotion and often have severe learning disabilities. Tan postulated that this is an example of "reverse evolution" (atavism). The proposed syndrome was featured in the 2006 BBC2 documentary The Family That Walks On All Fours.
A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem. The similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual genetic cause, it is clustering of a set of characteristic physiological features which define whether a syndrome is a ciliopathy.
Marinesco–Sjögren syndrome (MSS), sometimes spelled Marinescu–Sjögren syndrome, is a rare autosomal recessive disorder.
Congenital generalized lipodystrophy is an extremely rare autosomal recessive condition, characterized by an extreme scarcity of fat in the subcutaneous tissues. It is a type of lipodystrophy disorder where the magnitude of fat loss determines the severity of metabolic complications. Only 250 cases of the condition have been reported, and it is estimated that it occurs in 1 in 10 million people worldwide.
Gillespie syndrome, also called aniridia, cerebellar ataxia and mental deficiency, is a rare genetic disorder. The disorder is characterized by partial aniridia, ataxia, and, in most cases, intellectual disability. It is heterogeneous, inherited in either an autosomal dominant or autosomal recessive manner. Gillespie syndrome was first described by American ophthalmologist Fredrick Gillespie in 1965.
Goldberg–Shprintzen is a very rare connective tissue condition associated with mutations in KIAA1279 gene which encodes KIF-binding protein (KBP), a protein that may interact with microtubules and actin filaments. KBP may play a key role in cytoskeleton formation and neurite growth.
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders caused by genetic mutations and characterised by progressive atrophy of various parts of the brain such as the cerebellum or brainstem. Where known, these disorders are inherited in an autosomal recessive fashion. There is no known cure for PCH.
Autosomal recessive cerebellar ataxia describes a heterogeneous group of rare genetic disorders with an autosomal recessive inheritance pattern and a clinical phenotype involving cerebellar ataxia.
PMM2 deficiency or PMM2-CDG is a very rare genetic disorder caused by mutations in PMM2. It is an autosomal recessive disorder. A defective copy of the PMM2 gene is the most common cause of a disease called “congenital disorders of glycosylation” or “PMM2-CDG”. PMM2-CDG is the most common of a growing family of more than 130 extremely rare inherited metabolic disorders. Only about 1000 children and adults have been reported worldwide.
1 2 3 Verloes A, Lambotte C (February 1989). "Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis". American Journal of Medical Genetics. 32 (2): 227–32. doi:10.1002/ajmg.1320320217. PMID2929661.
1 2 Johnson CP, Walker WO, Palomo-González SA, Curry CJ (April 2006). "Mental retardation: diagnosis, management, and family support". Current Problems in Pediatric and Adolescent Health Care. 36 (4): 126–65. doi:10.1016/j.cppeds.2005.11.005. PMID16564466.
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