Thursday, November 26, 2015

Congenital insensitivity to pain

The girl who feels no pain was in the kitchen, stirring ramen noodles, when the spoon slipped from her hand and dropped into the pot of boiling water. It was a school night; the TV was on in the living room, and her mother was folding clothes on the couch. Without thinking, Ashlyn Blocker reached her right hand in to retrieve the spoon, then took her hand out of the water and stood looking at it under the oven light. She walked a few steps to the sink and ran cold water over all her faded white scars, then called to her mother, “I just put my fingers in!” Her mother, Tara Blocker, dropped the clothes and rushed to her daughter’s side. “Oh, my lord!” she said — after 13 years, that same old fear — and then she got some ice and gently pressed it against her daughter’s hand, relieved that the burn wasn’t worse.
“I showed her how to get another utensil and fish the spoon out,” Tara said with a weary laugh when she recounted the story to me two months later. “Another thing,” she said, “she’s starting to use flat irons for her hair, and those things get superhot.”...
When Ashlyn was 2, her mother had to wrap her hands to keep her from biting them.Credit Tara Blocker 

Without lifting her eyes from the crochet hooks in her hands, Ashlyn spoke up to add one detail to her mother’s story. “I was just thinking, What did I just do?” she said...

When she made an egg sandwich on the skillet, she pressed her hands onto the bread as Tara had taught her, to make sure it was cool before she put it into her mouth. She can feel warmth and coolness, but not the more extreme temperatures that would cause anyone else to recoil in pain.

There was the time she burned the flesh off the palms of her hands when she was 2. John was using a pressure-washer in the driveway and left its motor running; in the moments that they took their eyes off her, Ashlyn walked over and put her hands on the muffler. When she lifted them up the skin was seared away. There was the one about the fire ants that swarmed her in the backyard, biting her over a hundred times while she looked at them and yelled: “Bugs! Bugs!” There was the time she broke her ankle and ran around on it for two days before her parents realized something was wrong...

When she was born, she didn’t cry. She barely made a noise, staring out from her swaddling with a blank red face. When she developed terrible diaper rash, so raw that it made Tara wince to even wash her, the pediatrician gave instructions to change her formula and put cream on the rash and keep it dry. “I kept thinking, But she’s not crying,” Tara said. “The doctors dismissed it, but we’re thinking, What’s going on?”...

 At 6 months, Ashlyn’s left eye was swollen and bloodshot. The doctor suspected pink eye, but Ashlyn didn’t respond to the treatment, so they went to an ophthalmologist, who found a massive corneal abrasion. “And Ashlyn is just sitting there, happy as can be,” Tara recalled. The ophthalmologist assumed she had no corneal sensation in her eyes, and referred them to the Nemours Children’s Clinic in Jacksonville, Fla. It took a while to get an appointment, and before they made it to Jacksonville, Ashlyn rubbed big red splotches on her nose and almost chewed off part of her tongue with her emerging teeth...

“The doctor told us we were the only ones out there,” Tara said. “That it was so rare. He said to keep an eye on her and that they didn’t know much about it and couldn’t really be of any help. It was kinda like, ‘Good luck!’ ” ...

Over the next few years, Staud tested Ashlyn’s genetic material and eventually found two mutations in her SCN9A gene. That same gene, mutated in a different way, led to severe pain and chronic pain syndromes...

John and Tara had seen her say, “Ow!” when someone else was hurt. And Ashlyn yelped when her father described the time he put a nail straight through his thumb while he was building a chicken coop, but she had no idea why his face got red and his voice got loud and he held his thumb in the air. She said that over the years she studied the expressions other people made and learned to cringe when someone described something painful.
“Girl, what goes through your mind when you see someone hurt?” John asked her.
“I feel bad for them,” she said. “Because they go through the pain and I don’t. I would help them.”
“Define pain for you,” John said. “What does it mean for you?”
“I don’t know.”
“When you see someone else in pain, what do you associate?”
“That must really hurt.”
“What is hurt?”
Ashlyn squinted her eyes, as if in deep thought. She couldn’t answer him.


  1. Young Girl Cannot Feel Pain, Battles Rare Medical Condition CIPA | Good Morning America | ABC News

  2. Years ago, when I was in my pediatric neurology training, I did an open muscle biopsy on an adolescent male with congenital insensitivity to pain without anesthesia. It was a curious experience. When muscle tissue was being excised, he became a little restless, but otherwise in no way acknowledged pain or discomfort.

    A photo of this individual can be found in Swaiman and Wright, The Practice of Pediatric Neurology, 2nd ed, 1982, pg 226.

  3. Pérez-López LM, Cabrera-González M, Gutiérrez-de la Iglesia D, Ricart S,
    Knörr-Giménez G. Update Review and Clinical Presentation in Congenital
    Insensitivity to Pain and Anhidrosis. Case Rep Pediatr. 2015;2015:589852. Epub
    2015 Oct 22.


    Introduction. Congenital insensitivity to pain and anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV is an extremely rare syndrome. Three clinical findings define the syndrome: insensitivity to pain, impossibility to sweat, and mental retardation. This pathology is caused by a genetic mutation in the NTRK1 gene, which encodes a tyrosine receptor (TrkA) for nerve growth factor (NGF). Methods. The consultation of a child female in our center with CIPA and a tibia fracture in pseudoarthrosis encouraged us to carefully review literature and examine the therapeutic possibilities. A thorough review of literature published in Pubmed was done about CIPA and other connected medical issues mentioned in the paper. Conclusions. The therapeutic approach of CIPA remains unclear. The preventive approach remains the only possible treatment of CIPA. We propose two new important concepts in the therapeutic approach for these patients: (1) early surgical treatment for long bone fractures to prevent pseudoarthrosis and to allow early weight bearing, decreasing the risk of further osteopenia, and (2) bisphosphonates to avoid the progression of osteopenia and to reduce the number of consecutive fractures.

    From the article: The therapeutic approach to CIPA is still evolving and remains controversial. There is no definitive agreement regarding its management, and therapeutic options are restricted to treatment of symptoms and protection from self-mutilation, fractures, and wound infections, which may lead to amputation. Such limited treatment options imply potentially catastrophic consequences of the natural pathologic evolution of the disease. Fractures associated with CIPA may be devastating and deeply affect the patient's functionality. Surgical treatment provides stability to the focal point of the fracture, helping to provide definitive consolidation. Moreover, immobilization contributes to accelerated bone demineralization. Surgical fracture repair allows for early weight bearing, diminishing the risk of further osteopenia, which is also usually present in these patients as a part of their associated neurogenic arthropathy

  4. Emery EC, Habib AM, Cox JJ, Nicholas AK, Gribble FM, Woods CG, Reimann F.
    Novel SCN9A mutations underlying extreme pain phenotypes: unexpected
    electrophysiological and clinical phenotype correlations. J Neurosci. 2015 May


    The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype-phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.

  5. Amid the commotion, Tricia and Stephen blow on food to cool it before placing it on Gabby's plate. Something as simple as hot food is a challenge for Gabby, a bubbly and intelligent little girl who suffers from the rare condition, congenital insensitivity to pain with anhidrosis.

    Gabby cannot feel pain, making something as common as hot food dangerous...

    "Pain is a protection mechanism," Elghor said. "God gave us assistance so we can avoid harm. It's definitely a good thing."

    During her 9 years, Gabby has sustained a broken jaw, eye scratches so severe she is now legally blind and countless broken and sprained bones.

    Yet she has no concept of how badly her body is injured.

    "I feel pressure," Gabby said. "Cracking my head open feels the same as when I bang it."

    In addition, Gabby sweats very little. Doctors believe she only sweats 5-8 percent the amount of a normal person, her parents said. That makes it difficult to manage fevers. As a baby, they would put her in a cool bath and give her both children's Tylenol and Ibuprofen just to manage her body temperature.

    Yet, she and her parents work to live normal, fulfilling lives. She's a straight-A fourth-grader. She loves to read. Gabby also adores animals, and wants nothing more than a kitten (but her mother has allergies).

    Her parents have started the worldwide support group, A Gift of Pain, for those suffering from no pain. They have regular contact with 40 families from around the world...

    Her parents first noticed something was not normal when Gabby started teething. She bit into her fingers and tongue.

    But she never cried...
    The Gingrases also told Gabby's story to local and national media in hopes of finding families also dealing with no pain. They appeared on "20/20," "The Montel Williams Show," "Maury," "Oprah" and "Good Morning America."

  6. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G,
    Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S,
    Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006 Dec


    The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the condition as an autosomal-recessive trait to chromosome 2q24.3. This region contains the gene SCN9A, encoding the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons. Sequence analysis of SCN9A in affected individuals revealed three distinct homozygous nonsense mutations (S459X, I767X and W897X). We show that these mutations cause loss of function of Na(v)1.7 by co-expression of wild-type or mutant human Na(v)1.7 with sodium channel beta(1) and beta(2) subunits in HEK293 cells. In cells expressing mutant Na(v)1.7, the currents were no greater than background. Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans. These findings should stimulate the search for novel analgesics that selectively target this sodium channel subunit.

  7. Ma A, Turner A. A life without pain: congenital insensitivity to pain due to
    compound heterozygous SCN9A mutation. J Paediatr Child Health. 2012

    Our patient is an intelligent and healthy 2-year-old boy with a history of lack of response to painful stimuli. As an infant, he would bite into his tongue and lips, and had even self-extracted a tooth. In 2009, he had a left proximal tibial fracture . This did not heal well, and he subsequently developed non-union and osteomyelitis requiring prolonged treatment with intravenous antibiotics and open debridement and washout 6 months later. At no point was he noted to be in pain. He has also fractured his right tibia/fibula three times in 2010.

    Due to his recurrent hospital presentations with unwitnessed injuries, he was brought to the attention of the child protection team, and subsequent genetics and neurology involvement.

    His neurological examination was normal except for a failure to withdraw to painful stimuli. Nerve conduction studies were normal...

    SCN9A gene testing revealed a compound heterozygous mutation...

    Many people with CIP do not survive childhood due to recurrent injuries. Self-injury, burns, repeat fractures, osteomyelitis and accidental death are the main dangers of this disorder. Management consists of learning behaviours to reduce risk of injury and modifying the environment at home to minimise occult trauma. This is particularly difficult during childhood.