Common Clinical Features of ZTTK Syndrome

Below are lists of common clinical features that make up the phenotype (characteristics) of ZTTK Syndrome:

It is important to remember that while this list of ZTTK Syndrome features are commonly reported among patients, it does not mean that your child will have all of the symptoms listed or have all of the body systems listed impacted by the syndrome. It is also important to remember that this is not an exhaustive list, so it is possible for a ZTTK patient to have additional symptoms or complications not listed here.

• Cardiology: Aberrant Aorta; bilateral SVC; patent ductus arteriosus; ventricular and atrial septal defects; arrhythmias; hypoplastic left heart syndrome; coarctation of the aorta; heart murmur; transposition of great arteries; double-outlet right ventricle; mitral stenosis; tachycardia; high blood pressure; Tetralogy of Fallot; cardiomyopathy

• Cleft and Craniofacial: submucous cleft palate; laryngeal clefts; facial asymmetry; deep-set eyes; low-set ears; midface retraction

• Dermatology: eczema; dermatitis; sensitivity to sunlight; frequent staph infections; keratosis pilaris; Mast Cell Activation Syndrome; epidermolysis bullosa; hypohidrotic ectodermal dysplasia; hypohidrosis; dysplastic or missing fingernails; alopecia; severe reactions to bug bites; poor to slow healing of skin lesions/ burns/ injury

• Ear, Nose, and Throat: severe and repeated ear infections; ear anatomical anomalies requiring multiple sets or permanent ear tubes to promote hearing and proper ear drainage; laryngomalacia; born without breathe/ suck/ swallow reflex; aspiration issues; poor swallowing; hearing loss; hypersalivation; epiglottal webbing; frequent nose bleeds; sleep apnea;

• Endocrinology: Early onset and delayed puberty; adrenal insufficiency; thyroid disease; severe and rapidly decelerating hypoglycemia, which can result in unconsciousness; impaired function in glycolysis cycle; low cortisol; growth hormone deficiency; poor growth; short stature; carnitine deficiency; metabolic issues

• Gastroenterology: poor growth and slow weight gain; GERD; gastric dysmotility; often present need for feeding tube; bacterial overgrowth of the small bowel; gastroparesis; pancreatic insufficiency; poor appetite; sensitivity to foods and formulas; nausea and vomiting; dysphagia; failure to thrive that can be persistent and/ or to such an extreme that can potentially lead to starvation/ catabolic state that cannot be reversed despite medical intervention, which has been fatal for a few ZTTK patients

• Hematology: large red blood cells; abnormal CBC counts, including high and low WBC/ RBC/ Neutrophils; abnormally high B12, Vitamin A & E levels in the absence of vitamin supplementation; blood clots, including stroke; polycythemia; anemia requiring blood transfusions; low platelet counts requiring transfusions

• Immunology: low or poor response to vaccines, low immunoglobulin levels, including IgG, IgA, and IgM; immune deficiency requiring immunoglobulin therapy, including Common Variable Immune Deficiency (CVID) and Autoimmune Encephalitis; presentation of frequent respiratory infections, severe allergies, and severe reactions to common illnesses, such as strep are common in ZTTK patients

• Neurology: congenital brain abnormalities, including white matter loss, thinning/ partial/ total agenesis of the corpus callosum, thin optic nerves, etc.; epilepsy, including latent onset most often between the ages of 3 and 8 years old; intellectual and developmental delays that range from mild to severe; language delays that range from late onset, limited speech, and non-verbal; delayed developmental milestones; presentation of behaviors similar to Autism Spectrum Disorders, Bipolar, ADD/ ADHD, and Anxiety; hemiplegic migraines; auditory hallucinations; various forms of craniosynostosis; periventricular leukomalacia; periventricular heterotopia (PVNH); sudden onset of severe hydrocephalus resulting in cardiac arrest and tonsillar herniationof the brain, which has also proven fatal

• Ophthalmology: Cortical Visual Impairment (CVI); intermittent exotropia; strabismus; nystagmus; near and farsighted requiring prescription eyeglasses/ bifocals from an early age; corrective surgery for eye muscle weakness often necessary; vision loss

• Orthopedics/ Physical Medicine: scoliosis; kyphosis; extra bones; hypermobile joints; hypertonia; hypotonia; may require equipment for mobility and independence in mobility, such as walkers, gait trainers, AFO/ SMO/ insoles, weighted vests, etc.; osteoporosis; sacral dimple with and without tethered spinal cord

• Pulmonology: Frequent respiratory infections; severe and prolonged respiratory reactions and infections to common illnesses, such as the common cold; respiratory distress syndrome at birth requiring intubation and surfactant; need for respiratory support for poor airway function, airway clearance, and weak cough, including cough assist, rescue inhalers, nebulizer treatments, chest PT, and suction; lung scarring due to repeated respiratory infections and aspiration; asthma

• Therapy: Occupational, Physical, Vision, Speech, Developmental, and Behavioral Therapies are often necessary

• Urology: Ureter reflux, both bilateral and unilateral, ranging from mild to severe; kidney scarring and damage due to repeated infections due to urological abnormalities; severe urinary tract infections including pyelonephritis; frequent urinary tract infections requiring prophylactic antibiotic treatment; horseshoe kidney; kidney atrophy; cystic kidneys; hydronephrosis; dysplastic kidney

ZTTK Syndrome affects patients across a spectrum. Some patients are more severely affected by the syndrome than others. Current research indicates that the location of the mutation on the SON gene plays a significant role in the severity of the syndrome. It is also important to remember that even though ZTTK Syndrome is new and rare, the common clinical features listed above are overwhelmingly well-known to the medical community. So, while there is currently no overall treatment or cure for ZTTK, the medical complexities associated with the syndrome can be managed individually.

Less Common Features of ZTTK Syndrome

There are other features of ZTTK Syndrome that have been reported in patients and in literature that are less common but still notable. Again, please remember, that your ZTTK patient may or many not experience the features of ZTTK Syndrome, common or uncommon, in their entirety.

• Brain Tumors

• Bone Marrow Failure

• Bone Marrow Hypocellularity

• Shortened Telomeres

• Polycythemia Vera

• Aplastic Anemia

• Thalassemia

• Intestinal Failure 

Recommended Specialists

Each patient with ZTTK is different, and while some may not need to see all of the suggested specialists, there are some cases that will, if only to rule in or out typical complications of ZTTK. Some may need to be seen regularly throughout life for proper monitoring. Periodically check in with these specialists even though your initial evaluation is negative or shows no concerns. Things can change over time. Continued evaluations are encouraged.

• Genetics

• Pediatrics

• Neurology

• Gastrointerology

• Ear Nose & Throat

• Dental

• Pulmonology

• Cardiology

• Immunology

• Opthalmology (specializing in CVI)

• Urology

• Endocrinology

• Hematology

• Physicial Medicine & Rehabilitation

• Physical Therapy

• Occupational Therapy

• Speech Therapy

• Feeding Therapy

• Dietician

  Additional Recommendations

  Until the Diagnostic Manual for ZTTK Syndrome is published, it is suggested that all newly diagnosed families share the common features of ZTTK Syndrome with their child’s physicians and check-in to be evaluated for these features at least one time by the specialists listed in the “Common Clinical Features of ZTTK Syndrome.” If you are in need of an advocate to help you in coordinating these appointments for your child, please contact any board member or the ZTTK Ambassador for your country of residence. They can assist you in getting started in getting your child fully evaluated and support you as you begin your ZTTK journey.

  We also recommend to families to join our parent/ caregiver only Facebook group. If you need help getting linked up to our private, parent/ caregiver only Facebook group, please reach out to our Facebook Group Administrator, Kerry Tirrell at ktirrell@zttksonshinefoundation.org, or any Board member or ZTTK Ambassador. We take the confidentiality and privacy of our patients and their families very seriously, and we take the utmost care to ensure this in our Facebook group to provide a safe and welcoming families no matter where they are from or where they are on their ZTTK journey.

  We also want to remind families that it is important to develop positive relationships with your medical teams, as they will be instrumental in getting your child aligned with services and treatments to help them to live their very best life. However, it sometimes is necessary to be a strong advocate for your child and to help educate your medical, clinical, and educational teams about ZTTK Syndrome. This is especially important until more literature is published and there is more awareness in the medical, clinical, and educational settings about the syndrome. It is sometimes necessary to seek a second opinion, especially from teams that have seen other ZTTK patients. It is also sometimes necessary to have another ZTTK parent help you to advocate. We are happy that you have found us, and we are happy to help you and support you. We are stronger together! So, please know that you are not alone in any of this, and please reach out at any time with questions, concerns, and for help with advocating for your child.