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Congenital Insensitivity to Pain and Anhydrosis (CIPA) Syndrome; A Report of 4

Cases

Article  in  Iranian Journal of Pediatrics · September 2012

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 Iran J Pediatr
Case Report Sep 2012; Vol 22 (No 3), Pp: 412-416

Congenital Insensitivity to Pain and Anhydrosis (CIPA) Syndrome;

A Report of 4 Cases

Khadije Daneshjou, MD; Hanieh Jafarieh, MD*; Seyed-Reza Raaeskarami, MD

Department of Pediatrics, Imam Komoini Hospital, Tehran University of Medical Sciences, Tehran, Iran

Received: Dec 03, 2010; Final Revision: Sep 27, 2011; Accepted: Nov 20, 2011

Abstract
Background: Background: Congenital insensitivity to pain with anhidrosis (CIPA) is characterized by
recurrent episodes of infections and unexplained fever, anhidrosis (inability to sweat), and absence of
reaction to noxious stimuli, self-mutilating behavior, mental retardation and damages to oral structures.
Case Presentation: In this article, we have demonstrated the signs and symptoms of 4 children that refer to
the pediatrics department of the Imam Khomeini hospital and assay about their complications with this
disease. They mostly presented by recurrent osteomyelitis in their feet that severely controlled by antibiotic
therapy and even surgery. They had no pain sensation in spite of deep sore and infection.
Conclusion: This syndrome can be diagnosed by clinical and paraclinical tests together but it would be better
to confirm by genetic test. The diagnosis of this syndrome helps us to try for the better quality of life for the
patients and avoid unnecessary amputations.

Iranian Journal of Pediatrics, Volume 22 (Number 3), September 2012, Pages: 412-416

Key Words: CIPA Syndrome; Congenital Pain Insensitivity; Congenital Analgesia; Osteomyelitis

Introduction properly connected in parts of brain that receive

the pain messages. CIPA is extremely dangerous,
Pain alters the quality of life more than any other and in most cases the patient doesn’t live over age
health-related problem, and it is one of the of 25. Although some of them can live a fairly
implements of body protection. It interferes with normal life, they must constantly check for cuts,
sleep, mobility, nutrition, thought, sexual activity, bruises, self-mutilations, and other possible unfelt
emotional well-being, creativity, and self- injuries. Self-mutilation is an almost invariable
actualization. Congenital insensitivity to pain is a feature of this disorder, most often involving the
rare disorder, first described in 1932 by Dearborn teeth, lips, tongue, ears, eyes, nose, and fingers[2-4].
as Congenital pure analgesia. Congenital The odds of being born with this condition are
insensitivity to pain and anhydrosis (CIPA) is a about 1 in 125 million. People with CIPA also
very rare and extremely dangerous condition. cannot feel extreme temperatures, or sweat, both
People with CIPA cannot feel pain [1]. creating even more necessary care [5-7]. However,
Pain-sensing nerves in these patients are not in a patient with CIPA, the gene encoding the

* Corresponding Author;
Address: Pediatrics Division, Imam Khomini Hospital, Keshavarz Blvd, Tehran, Iran
E-mail: hanieh_j@yahoo.com
© 2012 by Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, All rights reserved.
Iran J Pediatr, Vol 22 (No 3); Sep 2012 413

Neurotrophic Tyrosine-Kinase receptor (NTRK1 infection by administering appropriate antibiotics

gene), is mutated in a way that interferes and halts and by the debridement of necrotic tissues to
the autophosphorylation process, therefore avoid limb amputation and to keep his quality of
stopping signals of pain and temperature from life as good as possible. He had also massive
being sent to the brain[8]. osteolysis in his mandible in which attemts were
made for appropriate dental procedures. Obvious,
self-mutilation, especially in his finger tips was
observed. Radiographies also revealed osteolysis
in his digit rum (Fig. 1). The other sites such as
Case Presentation lung, heart, abdomen and eyes were normal in
physical examination.
Case 1: A 12 year old boy presented with chronic Case 2: A 13 year old girl was referred to our
osteomyelitis. He was the fifth child of a department because of purulent discharge from a
consanguineous Iranian couple. In his birth deep sore in the talus and calcaneus of her right
history he had low Apgar score. There was no foot with history of recurrent osteomyelitis from
familial or hereditary disease in the family. the first months of life. She suffered from the
Pregnancy was normal. He had several absence of normal reaction to painful stimuli or
hospitalizations because of fever, seizure, heel heat. She occasionally had hyperthermia, and
sores and osteomyelitis (Fig. 1). He had no convulsions, high fever with abnormal
reaction to pain and could not feel pain or heat. electroencephalogram (EEG) and received
Brain CT scan and lumbar puncture findings were anticonvulsant drugs. There was no family history
normal. Metabolic and TORCH study were of special or hereditary diseases. She was the
negative. He is mentally retarded. The second child of related (first cousins) parents.
electromyography and nerve conduction velocity EMG-NCV, and immune tests were normal, and
(EMG and NCV) were normal. The immune tests viral markers negative. The patient had first
(complements, nitroblautetrazolium (NBT) test, experienced osteomyelitis when she was 3 years
immune globulins) and viral markers such as HBV, old in her buttocks and lumbar sites. Her last
HCV and HIV tests, blood gas and serum uric acid hospitalization was because of a resistant
were all normal. infection which did not respond to different
This patient was referred to us to control the antibiotics during the 3 preceding months.
infection of hill sore (an ulceration measuring Because of a harmful deformity in her heel and
10mm×10mm). We did our best to control the ineffective antibiotics, after an orthopedic consult,

Fig. 1: Finger tip osteolysis (right) and painless heel sore (left) in a 12 year old boy with CIPA syndrome
414 CIPA Syndrome, a Report of 4 Cases; H Jafarieh, et al

Fig. 2: Mandibular lysis, dental deformity (right) and post amputation cellulitis, recurrent infection (left) in
a 13 year old girl with CIPA syndrome

an amputation was performed (Fig. 2). Three A Family history revealed that her parents were
weeks after the amputation, however, she came cousins, and she was the fourth child of this family
back with massive cellulitis in the site of surgery with other children being normal. She had a
which progressed to the knee but she didn’t feel history of recurrent seizures which were treated
any pain. Our case had also significant mandibular as a metabolic disease since she was 4 months old
lysis and dental laisions. She was mentally for 4 years but there was no efficacy (Fig 3).
retarded. Osteolysis on her fingertips was seen, Case 4: A 7 year old girl, the child of consan-
but there was no sign of ocular disturbance (Fig. guineous (first cousins) parents, presented to the
2). pediatrics department in Imam Khomeini Hospital
Case 3: An 8-year-old girl was referred to the 6 years ago with swelling and erythema in her
pediatric department of Imam Khomeini Hospital right foot. Two siblings died at 2 and 3 years
because of fever, severe edema of right leg, of age because of unknown reasons. She had a
inflammation and purulent discharge from the
fistula in both legs especially right foot. She was
mentally retarded and hit her heel onto the
ground without any sensation of pain. She did not
respond to any painful stimuli or heat shock, but
could feel pressure and touch. There were some
scars on her skin on different sites of the body
which were, according to her parents, heat scars.
Hands and fingers showed signs of biting. Because
of chronic osteomyelitis, debridement of infectious
site was performed and antibiotics administered
several times. An EMG-NCV revealed a small fiber
disturbance and low amplitude of SNAPS due to a
skin problem. Immune tests, viral markers, blood
gas and uric acid level were normal. She had no
abnormality in ocular system. The EEG was mildly
abnormal, and she was treated by antiepileptic
drugs. Fig. 3: Irregularity and lysis of bones
Iran J Pediatr, Vol 22 (No 3); Sep 2012 415

history of several episodes of osteomyelitis and patients with CIPA because they do not feel it,
gangrene of the right and left foot. Further, she therefore do not know that they need to be
had osteolytic lesions in her mandible and the hospitalized[2,21,22]. Although Patients with CIPA
vestibular epithelium of the mandible was often experience trauma, bony fractures, and
destroyed. She was advised to do bone graft osteomyelitis because of insensitivity to pain.
surgery. All of her teeth fell out when she was 3 Therefore, such patients may undergo surgery
years old, and she had total alopecia from 6th such as osteotomy and amputation, in three of our
month of age. She also had history of recurrent cases the involved joint was saved without
fever, respiratory infection, cellulitis and amputation by utilizing conservative measures[23].
osteomyelitis. The disease was misdiagnosed as Three of our patients had severe osteolysis in the
chronic granulomatous disease (CGD) and treated oral cavity with osteolysis and finger tips
with intravenous immunoglobulin (IVIG). In this amputation as a result of self mutilation.
admission immunologic tests including Congenital insensitivity to pain with anhydrosis
complement, NBT, and electrophoresis of may be misdiagnosed as leprosy, based on similar
immunoglobulins were normal. Seven years ago symptoms of severe injuries to the hands and feet,
she became a candidate of amputation of her foot, which is not match with our cases according to
but as she didn’t agree, so received a graft and pin. other findings[24]. On the other hand, CIPA is the
Now she developed irregularity in the physeal and fourth type of hereditary sensory and autonomic
epiphyseal plate in tibia and fibula and had neuropathy (HSAN), known as HSAN IV (It is also
fracture of epiphyseal plate. Intelligence test was referred to as HSAN Type IV).
normal. The aim of reporting this syndrome is to make
physicians familiar with this condition and to
avoid unnecessary surgeries and even
amputations, to use conservative treatments and
make the diagnosis of this syndrome easier
Discussion without extra laboratory requests. Unfortunately
in our country we do not have the facility to
CIPA is an autosomal recessive disease[9], all of our confirm the diagnosis by genetic tests so we have
patients had consanguineous parents. There are to start treatment by clinical and paraclinical
few cases of insensitivity to pain described in the findings to make the patients quality of life better.
literature, but there is no standard treatment [2].
Patients with CIPA can live a fairly normal life
[4,7,10]. Three of our patients had mild mental

retardation and attended special schools.

However, there are certain precautions that need Conclusion
to be taken in order to ensure the safety of the
patient. The patient must constantly check for This study shows that we should notice the
cuts, bruises, self-mutilations, and other possible combination of some different signs and
unfelt injuries. Also, they must regularly visit their symptoms to find this syndromic disease.
doctor to receive a full work up to be sure that
they do not have any insensitive internal problems
that can be fatal. There are sixty documented cases
in the United States[1,9,11-17]. While some reports
indicate that these patients can only live up to five References
years and predict a poor prognosis for this
1. Dearborn G. A case of congenital pure analgesia.
disorder [4,18,19,20], all of our patients were older.
J Nerv Ment Dis 1932; 75:612-5.
The reasons for death among patients with CIPA
2. Rasmussen P. The congenital insensitivity-to-
are things that could otherwise be treated. A heat pain syndrome (analgesia congenita). Int J
attack, for instance, is much more dangerous for Paediatr Dent 1996; 6:117-22.
 416 CIPA Syndrome, a Report of 4 Cases; H Jafarieh, et al

3. Hall KH. Paediatric Orofacial Medicine and 14. Shaaban H, Bayat A, Davenport P, et al.
Pathology. 3rd ed. London: Chapman & Hall Necrotising fasciitis in an infant with congenital
Medical. 1994; pp 330-5. insensitivity to pain syndrome. British J Plast Surg
4. Narayanan V. Oral and maxillofacial 2002;55(2):160-3.
manifestations of hereditary sensory neuropathy. 15. Auer-Grumbach M, De Jonghe P, Verhoeven K, et
Br J Oral Maxillofac Surg 1996; 34:446-9. al. Autossomal dominant inherited neuropathies
5. Nagasako EM, Oaklander AL, Dworkin RH. with prominent sensory loss and mutilations.
Congenital insensitivity to pain: An update. Pain Arch Neurol 2003;60(3):329-32.
2003; 101:213-9. 16. Bonkowsky JL, Johnson CC, Smith AG, Swoboda
6. Dick PJ. Neuronal atrophy and degeneration KJ. An infant with primary tooth loss and palmar
predominantly affecting peripheral sensory and hyperkeratosis: a novel mutation in the NTRK1
autonomic neurons. In: Dick PJ, Thomas PK, gene causing congenital insensitivity to pain with
Griffin JW, Low, PA, Podreslo, JC eds. Peripheral anhidrosis. Pediatrics 2003;112(3 pt 1):237-41.
Neuropathy. 17th ed. Philadelphia: Saunders. 17. Boraz RA. Familial dysautonomia, Riley-Day
1993; pp 1065-93. syndrome. J Dent Child 1984;51(1):64-5.
7. Emad MR, Raissi GR. Congenital insensitivity to 18. Rakocz M, Frand M, Brand N. Familial
pain with anhidrosis. Electromyogr Clin dysautonomia with Riga-Fede’s disease: report of
Neurophysiol 2003; 43:409-41. case. J Dent Child 1987;54(1):57-9.
8. Mardy S, Miura Y, Endo F, et al. Congenital 19. Nicholson GA, Dawkins JL, Blair IP, Kennerson
Insensitivity to pain with anhidrosis (CIPA): effect ML, et al. The gene for hereditary sensory
of TRKA (NTRK1) missense mutations on neuropathy type I (HSN-I) maps to chromosome
autophosphorylation of the receptor tyrosine kinase 9q22.1-q22.3. Nat Genet 1996;13(1):101-4.
for nerve growth factor. Hum Mol Genet
20. lrod FB, Hilz MJ. Inherited autonomic
2011;10(3):179-88.
neuropathies. Semin Neurol 2003;23(4):381-90.
9. Kouvelas N, Terzoglou C. Congenital insensitivity
21. Verhoeven K, Coen K, De Vriendt E, et al. SPTLC1
to pain with anhidrosis. Ped Dent 1989;11(1):47-
mutation in twin sisters with hereditary sensory
51.
neuropathy type 1. Neurology 2004;62(6):1001-
10. Thompson CC, Park RI, Prescott Gh. Oral 2.
manifestation of the congenital insensitivity-to-
22. Lafreniere RG, MacDonald M, Dube M, et al.
pain syndrome. Oral Surg Oral Med Oral Pathol
Identification of a novel gene (HSN2) causing
1980;50(3):220-5.
hereditary sensory and autonomic neuropathy
11. Littlewood SJ, Mitchell L. The dental problems type II through the study of Canadian genetic
and management of a patient suffering from isolates. Am J Hum Genet 2004;74(5):1064-73.
congenital insensitivity to pain. Int J Paediatr
23. Smael Labib, Mohamed Adnane Berdai, Sanae
Dent 1998;8(1):47-50.
abourazzak, Mustapha Hida, Mustapha Harandou.
12. Rosenberg S, Nagahashi Marie SK, Kliemann S. Congenital insensitivity to pain with anhydrosis:
Congenital insensitivity to pain with anhidrosis report of a family case. Pan Afr Med J 2011;9:33.
(hereditary sensory and autonomic neuropathy
24. Congenital insensitivity to pain with anhidrosis
type IV). Pediat Neurol 1994;11(1):50-6. Available at: http://en.wikipedia.org/wiki/
13. Brahim JS, Roberts MW, McDonald H. Oral and Congenital_insensitivity_to_pain_with_anhidrosis
maxillofacial complications associated with #Differential_diagnosis. Access date: Nov 2010.
congenital sensory neuropathy with anhidrosis.
J Oral Maxillofac Surg 1987;45(4):331-4.

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