CIPA case study

CONGENITAL INSENSITIVITY TO PAIN WITH ANHIDROSIS

FAIZA FIRASATH HUDA TAHREEM M.SUJIN SURESH GCM FINAL YEARS R20

01

INTRODUCTION

As we know that genetic disorders are disorders caused by change on mutation in an individual’s DNA sequence so just like that congenital insensitivity to pain with anhidrosis (CIPA) otherwise known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV) is a rare autosomal recessive disorder caused by mutation in the NTRK1 GENE. The NTRK1 GENE gives body instructions to make proteins that are important for development and survival of nerve cells – specially those that carry information about pain, temperature and touch.

• The NTRK1 is a gene –encoding TRKA {tropomyosin-related kinase A} present on chromosome 1 which is a receptor tyrosine kinase for NGF.
• NGF is a neurotrophic factor which induces nerve growth and promotes survival of embryonic and sympathetic NGF- dependent neurons.
• It is also considered as an inflammatory mediator of pain and inflammation in adults.
• Nociceptive sensory neurons are NGF dependent that respond to tissue damage and are vital for survival and maintenance of human body.
• NTRK1 is auto phosphorylated with NGF, thus producing several intracellular signalling transduction pathways. When there is a loss-of-function mutation in NTRK1 gene it also causes defects in the TRKA-NGF signal transduction causing the death of many NGF-dependent neurons due to which the person suffers from CIPA.
• CIPA is the first disease to arise due to failure of survival of NGF- dependent neurons, most likely due to apoptosis of neurons in developing stage

AGE GROUP

INCIDENCE AND PREVALENCE

The most common ages for symptoms of a disease to begin is called age of onset.

• The incidence of this disorder has been estimated to be 1 in 25, 000 population .

• CIPA is a very rare disease; there are only around 60 documented cases in the United States and around 300 worldwide . Since it is a genetic disease, CIPA is more likely to occur in homogeneous societies.

• It is most common among Negev Arabs aka Negev Bedouins.

Birth-4 weeks Infant- 1-23 months Child- 2-11 years

Approximately 20% of people with CIPA die of hyperthermia by age 3

SYMPTOMS

⦁ Several bite marks on the tongue and fingers without response. ⦁ Some bite the tip of their tongue completely off by the time they are two without realizing it. ⦁ Overheating of body during hot weather. ⦁ Severe ulcers. ⦁ Lack of sweat glands makes the skin thick and leathery even cannot control body temperature or naturally cool their bodies. ⦁ Fractures in the body. ⦁ Chronic infections in the bones and joints. ⦁ Multiple joint destructions in the body secondary to osteomyelitis. ⦁ Osteomyelitis and joint deformities that can lead to amputations. ⦁ Infections and scratches of the eye. ⦁ Multiple hand lesions.

02

case presentation

CLINICAL PRESENTATION

A 2.5-year-old boy was referred to the pediatrics clinic with severe self-mutilating injuries to his hands, feet, tongue and oral mucosa caused by unconscious biting He is the second child of cousin parents and the product of a term, normal vaginal delivery with a birth weight of 3300 gr. At two-months of age, he was admitted to the hospital as a result of fever and convulsion. The patient continued to have fever throughout his hospital stay and evaluation for the etiology of prolonged fever was done and abnormal results were not seen in any of the diagnostic tests The parents complained that the child showed no response to any kind of injury including pinpricking, burning, hitting and cutting. The boy had never complained of painful sensation and his hands or feet were burned by heater flame or hot water repeatedly.

He had a right third metatarsal fracture without reason when he was 2.5 years old that was managed on an outpatient basis and caused edema and deformity in his right foot. Teething had started at seven months of age, but because of biting and ulcerative lesions in the gums, his teeth had started to shed at 1.5 years of age. On examination, he had 12 kilograms weight (10th percentile), 92 centimeter height (75th percentile) and 48 centimeter head circumference (10th percentile) and a normal blood pressure without orthostatic hypotension. Ulcerative lesions were seen in his fingers, toes and mouth that were caused by self-biting . Fungiform papillae on the tongue were present. In addition, keratosis and thick and dry skin in the palms of his hands and soles of feet were visible . He had red eyes and corneal ulcer. The deformity as Charcot joint (neuropathic osteoarthropathy) was observed in the right ankle due to repeated trauma .

Ulcerative lesions of the fingers due to self-biting and palmar keratosis

Charcot joint in the right ankle

03

diagnosis

Many diagnostic tests were performed to identify what the patient was suffering from , most of the test that were done showed normal results .Neurologic examination revealed normal function of the cranial nerves. The light response of pupils and deep tendon reflexes (DTR) were normal and plantar reflex was flexor bilaterally. Family history was also negative and they had no sign of hereditary disease. The result of CBC, uric acid, serum glucose, liver, renal and thyroid function tests, serum lactate, ammonia, creatinine phosphokinase level and chromatography of amino acids, blood smear, bone marrow aspiration and culture, Wright and Vidal test, abdominal sonography and brain CT scan were all normal. Even nerve conduction velocity (NCV) was normal and only brain MRI showed mild brain atrophy.

Finally CIPA could be diagnosed through neuropathological exam in electron microscopy where the absence of unmyelinated fibers and reduction in the number of small myelinated fibers was found in patient and these are the common features of someone suffering from CIPA . and normal distribution of large myelinated fibers) and Detecting of mutations on the NTRK1 gene represents is the last diagnostic step after confirming the absence of unmyelinated fibers .

04

MANAGEMENT

MANAGEMENT AND TREATMENT Visual and eye follow-up regularly in CIPA patients for early diagnosis and timely treatment of corneal neurotrophic ulcer and prevention of corneal and vision-threatening complications such as scarring and perforation. Early diagnosis and specific dental management in CIPA patients may be useful in reducing the frequency and severity and also preventing self-mutilation complications of this disorder Osteoarticular and orthopedic complications of CIPA patients are one of the most common problems in such patients that need early recognition and timely treatment and also prevention of accidental injuries Prenatal screening is the sole accessible option to prevent the birth of an affected child as no cure is available While there is no cure for CIPA, there are experimental treatments using naloxone. This chemical works within the group of cells that recieves the message to initiate the sensation of pain, heat or cold.

05

CONCLUSION

CONCLUSION CIPA should be considered as a diagnosis in any child presenting with a history of poor or absent responses to painful stimuli.This condition can be easily missed because it is not well known by medical community. Children with CIPA often injure themselves severely, and the injury may go unnoticed, resulting in permanent damage.

Overall, early recognition of the disease is important. The treatment for this condition is focused more on the prevention of bone injuries and joint infection, as opposed to a cure. There are no standard techniques or guidelines available to treat this rare disease. Effective CIPA treatment is built around family education and patient training