Beyond pain: early Hypotonia and growth failure in congenital insensitivity to pain with Anhidrosis

Abstract

Congenital insensitivity to pain with anhidrosis is a rare genetic disorder caused by mutations in the neurotrophic receptor tyrosine kinase 1 gene, characterized by absent pain perception and inability to sweat. Early recognition is essential to prevent severe complications. We report a seven-month-old boy presenting with poor growth, hypotonia, and delayed motor development. Initial metabolic and neuromuscular evaluations, including nerve conduction studies and brain imaging, were normal. His growth remained at the minus three standard deviation centile. By twelve months, additional features emerged, including self-injurious behavior, lack of response to injury, and reduced sweating. A positive family history prompted genetic testing, which confirmed a pathogenic variant in the neurotrophic receptor tyrosine kinase 1 gene. This case highlights that early nonspecific features may precede classical manifestations, emphasizing the importance of clinical vigilance, family history, and early genetic testing to enable timely multidisciplinary management.

Introduction

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is a rare inherited disorder affecting sensory and autonomic nerves. Patients are unable to perceive pain, temperature and have anhidrosis, resulting in impaired thermoregulation and recurrent unnoticed injuries. The condition is most associated with mutations in the neurotrophic receptor tyrosine kinase 1 (NTRK1) gene, which encodes the Tropomyosin-related kinase A (TrkA) receptor involved in nerve growth factor signaling and development of pain-sensing neurons [1].

Clinical manifestations may vary, and early presentations can be nonspecific, including developmental delay and hypotonia, which may delay diagnosis. Early recognition and genetic confirmation are important to guide preventive multidisciplinary management and reduce complications [2].

Case report

A 7-month-old boy presented with growth faltering, generalized hypotonia and gross motor delay. He was the third child in the family, born at 37 weeks’ gestation via spontaneous vaginal delivery following an uncomplicated pregnancy and delivery. His birth weight was 2.65 kg, which was appropriate for gestational age. However, his weight began to cross below the −2 SD growth centile from 2 months of age. He had been formula-fed since birth and, at 7 months of age, was taking approximately 250 mL (5 oz) of formula milk seven times daily. On presentation, his weight was 5.6 kg (−3 SD). His parents also reported persistent feeding refusal after complementary feeding was introduced at 6 months of age. Despite repeated attempts with a variety of solid foods, including porridge, infant cereal, and fruits, the child consistently spat out the food and refused weaning feeds.

At 7 months of age, he was only able to roll from prone to supine which was developmentally inappropriate. Other developmental domains were age appropriate, and no dysmorphic features were observed. In view of the hypotonia, a comprehensive evaluation was undertaken to exclude metabolic and neuromuscular causes. Blood investigations were performed, and both magnetic resonance imaging (MRI) of the brain and nerve conduction studies were arranged. The MRI and nerve conduction study results were normal, and laboratory findings did not demonstrate any significant abnormalities.

At subsequent follow-up at 1 year of age, he continued to exhibit hypotonia and gross motor delay. His weight tracked consistently along the −3 SD centile line. During this period, he also began demonstrating self-mutilating behaviors, including repetitive head banging and biting of his tongue and fingers until bleeding occurred. His parents reported that he did not cry following falls or apparent injuries and appeared insensitive to painful stimuli. Physical examination revealed multiple wounds over the palm, ear pinna, shin and toes (Figs 1–4). Despite visible injuries, he displayed no signs of discomfort.

Figure 1.

Wound over the right ear pinna.

Figure 4.

Wound over the left shin.

Figure 2.

Laceration wound over the palm of left index finger.

Figure 3.

Wound over the right toes.

Further history revealed features suggestive of autonomic dysfunction. His parents reported that he rarely perspired, even when exposed to outdoor temperatures of approximately 35°C, compared with his siblings who perspired normally under similar environmental conditions. His mother also consistently felt that his body was unusually warm to touch. However, repeated home temperature measurements using an ear thermometer consistently recorded temperatures below 37.5°C. There was no history of documented hyperthermia or recurrent unexplained fever.

The mother later disclosed that a cousin had recently been diagnosed with CIPA. Considering the child’s clinical features and positive family history, genetic testing was arranged. Molecular analysis identified a likely pathogenic variant in the NTRK1 gene, confirming the diagnosis of CIPA.

Management in this patient is primarily supportive and preventive, as there is no curative therapy. The patient was referred to and is being followed up by a multidisciplinary team involving pediatrics, orthopedics, dentistry, physiotherapy and occupational therapy, in order to prevent complications, preserve function, and optimize long-term outcomes. Given the patient’s impaired thermoregulation and residence in a tropical climate, the parents were also counselled regarding heat avoidance strategies and regular home temperature monitoring.

Discussion

This case shows that CIPA may begin with unclear symptoms such as poor growth and low muscle tone. Later, more typical signs appear, such as painless injuries and self-harming behaviors. An important point in this case is that the nerve conduction study was normal, which may wrongly suggest that there is no nerve problem. However, CIPA mainly affects small nerve fibers and the autonomic system, while routine nerve conduction tests only assess larger nerves. Therefore, the test results can appear normal even when the disease is present. Other tests, such as autonomic function tests (e.g. sympathetic skin response, Quantitative Sudomotor Axon Reflex Test (QSART)) and skin biopsy to assess nerve fiber density, can be more useful in detecting small fiber nerve problems, especially when the diagnosis is suspected before or alongside genetic testing [3].

The child’s ongoing low muscle tone and delayed motor development before the appearance of self-injury suggest two important points. First, these early symptoms can be part of CIPA, as some patients are known to have developmental delay and behavioral problems that may require rehabilitation support [4]. Second, the condition can vary depending on the type of mutation in the NTRK1 gene. Different mutations can affect nerve function in different ways, which may explain why patients show differences in their development and cognitive abilities [3].

Growth faltering has been reported in children with CIPA, although it is not a cardinal feature, and is likely multifactorial, including feeding difficulties, unrecognized injuries, infections, increased metabolic demands, and developmental impairment [5, 6]. In our patient, birth weight was appropriate, but weight fell below −2 SD by 2 months, before self-mutilation began. Although feeding refusal developed after 6 months, formula intake remained adequate and significant oral injury had not yet occurred, suggesting that early growth faltering was not solely due to oral trauma but likely reflected both feeding difficulties and the underlying disease.

Anhidrosis is a hallmark feature of CIPA and increases the risk of hyperthermia due to impaired heat dissipation. Despite living in a tropical climate with temperatures up to 35°C, our patient had no documented hyperthermia or recurrent fever. However, his reduced sweating and frequent warmth suggest underlying autonomic dysfunction, indicating that significant anhidrosis can occur without overt fever. Parents should be advised on heat avoidance, adequate hydration, appropriate clothing, use of cooling methods, and regular temperature monitoring, with prompt cooling if body temperature rises above normal [4, 7].

The diagnosis became clearer when the child started showing self-harming behaviors and when a family history was identified. CIPA can look similar to other conditions that cause loss of pain sensation. For example, SCN9A-related disorders usually do not affect sweating, while HSAN type V may have pain loss but often still have normal sweating and better intellectual function. Therefore, doctors should consider features like lack of sweating, family history, and how the symptoms develop over time to guide appropriate genetic testing [8].

There is currently no cure for CIPA, as it is not possible to restore the ability to feel pain or to sweat. Therefore, treatment mainly focuses on prevention and supportive care, and it requires a multidisciplinary team approach to prevent injuries and complications. This includes protecting the child from repeated trauma, as they are unable to feel pain. Special attention should be given to preventing self-injury, especially oral self-biting, which may require dental interventions such as protective devices or regular dental monitoring. Regular screening is also important to detect hidden problems early, such as fractures or joint damage (Charcot joints), which may go unnoticed due to lack of pain. Proper skin and wound care are essential to prevent infections. Eye protection is also important, as reduced sensation can increase the risk of eye injury. In addition, careful temperature monitoring is needed because the inability to sweat increases the risk of overheating (hyperthermia), especially in hot environments [4].

Identifying the condition before serious complications occur allows healthcare providers to start regular monitoring and provide proper education to parents or caregivers. This helps families understand how to prevent injuries, recognize warning signs, and manage the child safely in daily life. Overall, a structured and proactive approach can significantly reduce complications and improve the child’s quality of life [4].

This case demonstrates that CIPA can present with subtle developmental symptoms before the characteristic findings of painless injury and self-mutilation emerge. Normal nerve conduction studies do not exclude the diagnosis. Early clinical suspicion, careful family history assessment, and timely genetic testing are essential to establish the diagnosis and initiate multidisciplinary preventive care and counseling.

Conflicts of interest

The author and all co-authors declare that they have no conflicts of interest.

Funding

None declared.

Ethical approval

Ethical approval was not required for publication of this case report.

Consent

Written informed consent for publication of this case report and accompanying images was obtained from the patient’s parent/legal guardian.

Guarantor

Nani Draman.