Antibiotics are the primary treatment. The specific approach to their use is dependent on the individual affected and the stage of the disease. For most people with early localized infection, oral administration of doxycycline is widely recommended as the first choice, as it is effective against not only "Borrelia" bacteria but also a variety of other illnesses carried by ticks. Doxycycline is contraindicated in children younger than eight years of age and women who are pregnant or breastfeeding; alternatives to doxycycline are amoxicillin, cefuroxime axetil, and azithromycin. Individuals with early disseminated or late infection may have symptomatic cardiac disease, refractory Lyme arthritis, or neurologic symptoms like meningitis or encephalitis. Intravenous administration of ceftriaxone is recommended as the first choice in these cases; cefotaxime and doxycycline are available as alternatives.

These treatment regimens last from one to four weeks. If joint swelling persists or returns, a second round of antibiotics may be considered. Outside of that, a prolonged antibiotic regimen lasting more than 28 days is not recommended as no clinical evidence shows it to be effective. IgM and IgG antibody levels may be elevated for years even after successful treatment with antibiotics. As antibody levels are not indicative of treatment success, testing for them is not recommended.

Attached ticks should be removed promptly, as removal within 36 hours can reduce transmission rates. Folk remedies for tick removal tend to be ineffective, offer no advantages in preventing the transfer of disease, and may increase the risks of transmission or infection. The best method is simply to pull the tick out with tweezers as close to the skin as possible, without twisting, and avoiding crushing the body of the tick or removing the head from the tick's body. The risk of infection increases with the time the tick is attached, and if a tick is attached for less than 24 hours, infection is unlikely. However, since these ticks are very small, especially in the nymph stage, prompt detection is quite difficult. The Australian Society of Clinical Immunology recommends against using tweezers to remove ticks but rather to kill the tick first by using a product to rapidly freeze the tick to prevent it from injecting more allergen-containing saliva. In a tick allergic person, the tick should be killed and removed in a safe place (e.g. an emergency department of a hospital).

The Baggio–Yoshinari syndrome (BYS), formerly known as the Brazilian Lyme-like disease and Brazilian human borreliosis, is a disease transmitted by the "Amblyomma cajennense" tick, but the organism that causes the infection is still unknown. Clinical features resemble those of Lyme disease (LD).

In 1989, Brazilian researchers Professors Domingos Baggio (an entomologist from the Biomedical Sciences Institute of the University of São Paulo), Paulo Yasuda (a microbiologist from the same institute) and Natalino Hajime Yoshinari (a physician from the Rheumatology Department at University of São Paulo's Medical School) started research on Lyme disease in Brazil, by suggestion of Dr. Allen Steere. At that time, LD was almost unknown among Brazilian physicians.

The first cases were described in Brazil in 1992 in siblings from Cotia, São Paulo that developed symptoms as a migrating redness, general flu-like symptoms and arthritis after being bitten by ticks. Although the symptoms were similar to those presented by patients of Lyme disease, clinical and laboratorial results were considerably different. Ticks of the "Ixodes ricinus" complex were not found at the risk areas; bacteria from the "Borrelia burgdorferi" sensu lato complex —that cause Lyme disease— were not found in biological fluids and tissues of the siblings. Blood analysis of the patients on electron microscopy exhibited structures resembling microorganisms of the spirochaete phylum. For these reasons, the Brazilian zoonosis was considered a new disease and named Baggio–Yoshinari Syndrome (BYS), defined as: "Exotic and emerging Brazilian infectious disease, transmitted by ticks not belonging to the "Ixodes ricinus" complex, caused by latent spirochetes with atypical morphology, which originates LD-like symptoms, except for occurrence of relapsing episodes and auto-immune disorders".

Harlequin syndrome is not debilitating so treatment is not normally necessary. In cases where the individual may feel socially embarrassed, contralateral sympathectomy may be considered, although compensatory flushing and sweating of other parts of the body may occur. In contralateral sympathectomy, the nerve bundles that cause the flushing in the face are interrupted. This procedure causes both sides of the face to no longer flush or sweat. Since symptoms of Harlequin syndrome do not typically impair a person’s daily life, this treatment is only recommended if a person is very uncomfortable with the flushing and sweating associated with the syndrome.

There is no medical treatment for either syndrome but there are some recommendations that can help with prevention or early identification of some of the problems. Children with either syndrome should have their hearing tested, and adults should be aware that the hearing loss may not develop until the adult years. Yearly visits to an ophthalmologist or other eye care professional who has been informed of the diagnosis of Stickler or Marshall syndrome is important for all affected individuals. Children should have the opportunity to have myopia corrected as early as possible, and treatment for cataracts or detached retinas may be more effective with early identification. Support for the joints is especially important during sports, and some recommend that contact sports should be avoided by those who have very loose joints.

As of 2017, data on optimal treatment was limited. Therapies with hormones is the standard of care, namely adrenocorticotrophic hormone (ACTH), or oral

corticosteroids such as prednisone. Vigabatrin is also a common consideration, though there is a risk of visual field loss with long term use. The high cost of ACTH leads doctors to avoid it in the US; higher dose prednisone appears to generate equivalent outcomes.

As of 2017 data from clinical trials of the ketogenic diet for treating infantile spams was inconsistent; most trials were as a second-line therapy after failure of drug treatment, and as of 2017 it had not been explored as a first line treatment in an adequately designed clinical trial.

Orofaciodigital syndrome type 1 can be treated with reconstructive surgery or the affected parts of the body. Surgery of cleft palate, tongue nodules, additional teeth, accessory frenulae, and orthodontia for malocclusion. Routine treatment for patients with renal disease and seizures may also be necessary. Speech therapy and special education in the later development may also be used as management.

At the 2005 American Society of Human Genetics meeting, Francis Collins gave a presentation about a treatment he devised for children affected by Progeria. He discussed how farnesyltransferase inhibitor (FTI) affects H-Ras. After his presentation, members of the Costello Syndrome Family Network discussed the possibility of FTIs helping children with Costello syndrome. Mark Kieran, who presented at the 1st International Costello Syndrome Research Symposium in 2007, agreed that FTIs might help children with Costello syndrome. He discussed with Costello advocates what he had learned in establishing and running the Progeria clinical trial with an FTI, to help them consider next steps.

Another medication that affects H-Ras is Lovastatin, which is planned as a treatment for neurofibromatosis type I. When this was reported in mainstream news, the Costello Syndrome Professional Advisory Board was asked about its use in Costello Syndrome. Research into the effects of Lovastatin was linked with Alcino Silva, who presented his findings at the 2007 symposium. Silva also believed that the medication he was studying could help children with Costello syndrome with cognition.

A third medication that might help children with Costello syndrome is a MEK inhibitor that helps inhibit the pathway closer to the cell nucleus.

In patients that have already been diagnosed with sarcoidosis, Heerfordt syndrome can be inferred from the major symptoms of the syndrome, which include parotitis, fever, and facial nerve palsy. In cases of parotitis, ultrasound-guided biopsy is used to exclude the possibility of lymphoma. There are many possible causes of facial nerve palsy, including Lyme disease, HIV, Melkersson–Rosenthal syndrome, schwannoma, and Bell's palsy. Heerfordt syndrome exhibits spontaneous remission. Treatments for sarcoidosis include corticosteroids and immunosuppressive drugs.

Heerfordt syndrome, also referred to as uveoparotid fever, Heerfordt–Mylius syndrome, Heerfordt–Waldenström syndrome, and Waldenström's uveoparotitis, is a rare manifestation of sarcoidosis. The symptoms include inflammation of the eye (uveitis), swelling of the parotid gland, chronic fever, and in some cases, of the facial nerves.

As there is no known cure, Loeys–Dietz syndrome is a lifelong condition. Due to the high risk of death from aortic aneurysm rupture, patients should be followed closely to monitor aneurysm formation, which can then be corrected with interventional radiology or vascular surgery.

Previous research in laboratory mice has suggested that the angiotensin II receptor antagonist losartan, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome. A large clinical trial sponsored by the National Institutes of Health is currently underway to explore the use of losartan to prevent aneurysms in Marfan syndrome patients. Both Marfan syndrome and Loeys–Dietz syndrome are associated with increased TGF-beta signaling in the vessel wall. Therefore, losartan also holds promise for the treatment of Loeys–Dietz syndrome. In those patients in which losartan is not halting the growth of the aorta, irbesartan has been shown to work and is currently also being studied and prescribed for some patients with this condition.

If an increased heart rate is present, atenolol is sometimes prescribed to reduce the heart rate to prevent any extra pressure on the tissue of the aorta. Likewise, strenuous physical activity is discouraged in patients, especially weight lifting and contact sports.

In terms of treatment/management one should observe what signs or symptoms are present and therefore treat those as there is no other current guideline. The affected individual should be monitored for cancer of:

- Thyroid

- Breast

- Renal

Many professionals that are likely to be involved in the treatment of those with Stickler's syndrome, include anesthesiologists, oral and maxillofacial surgeons; craniofacial surgeons; ear, nose, and throat specialists, ophthalmologists, optometrists, audiologists, speech pathologists, physical therapists and rheumatologists.

Bloom syndrome has no specific treatment; however, avoiding sun exposure and using sunscreens can help prevent some of the cutaneous changes associated with photo-sensitivity. Efforts to minimize exposure to other known environmental mutagens are also advisable.

In terms of treatment of oculocerebrorenal syndrome for those individuals who are affected by this condition includes the following:

- Glaucoma control (via medication)

- Nasogastric tube feeding

- Physical therapy

- Clomipramine

- Potassium citrate

Treatment for the disease itself is nonexistent, but there are options for most of the symptoms. For example, one suffering from hearing loss would be given hearing aids, and those with Hirschsprung’s disorder can be treated with a colostomy.

Similar to all genetic diseases Aarskog–Scott syndrome cannot be cured, although numerous treatments exist to increase the quality of life.

Surgery may be required to correct some of the anomalies, and orthodontic treatment may be used to correct some of the facial abnormalities. Trials of growth hormone have been effective to treat short stature in this disorder.

Treatment of Roberts syndrome is individualized and specifically aimed at improving the quality of life for those afflicted with the disorder. Some of the possible treatments include: surgery for the cleft lip and palate, correction of limb abnormalities (also through surgery), and improvement in prehensile hand grasp development.

If a contracture is less than 30 degrees, it may not interfere with normal functioning. The common treatment is splinting and occupational therapy. Surgery is the last option for most cases as the result may not be satisfactory.

Treatment of Aicardi syndrome primarily involves management of seizures and early/continuing intervention programs for developmental delays.

Additional comorbidities and complications sometimes seen with Aicardi syndrome include porencephalic cysts and hydrocephalus, and gastro-intestinal problems. Treatment for porencephalic cysts and/or hydrocephalus is often via a shunt or endoscopic of the cysts, though some require no treatment. Placement of a feeding tube, fundoplication, and surgeries to correct hernias or other gastrointestinal structural problems are sometimes used to treat gastro-intestinal issues.

Café au lait spots can be removed with lasers. Results are variable as the spots are often not completely removed or can come back after treatment. Often, a test spot is treated first to help predict the likelihood of treatment success.

Some people may have some mental slowness, but children with this condition often have good social skills. Some males may have problems with fertility.

Surgery is typically used to correct structural heart defects and syndactyly. Propanolol or beta-adrenergic blockers are often prescribed as well as insertion of a pacemaker to maintain proper heart rhythm. With the characterization of Timothy syndrome mutations indicating that they cause defects in calcium currents, it has been suggested that calcium channel blockers may be effective as a therapeutic agent.

There are two lines of treatment for Pisa syndrome. The first line entails discontinuation or reduction in dose of the antipsychotic drug(s). The second line of treatment is an anticholinergic medication. A pharmacological therapy for Pisa syndrome caused by prolonged use of antipsychotic drugs has not been established yet.