Congenital idiopathic generalized anhidrosis: A rare cause of recurrent fever of unknown origin in children and review of existing literature.

Sir,

Anhidrosis refers to the failure in sweat production in response to physical, thermal, or chemical stimuli. This disorder includes congenital causes (hypohidrotic ectodermal dysplasia (HED), congenital insensitivity to pain and anhidrosis, and Fabry disease) and the acquired variety – idiopathic and secondary causes (neuropathy, endocrinopathy, metabolic disorders, and drug induced).[1] Cases of congenital generalized anhidrosis that occurs without any associated problems have been rarely described in the literature. Here, we report a child with congenital idiopathic generalized anhidrosis (CIGA) and succinctly review the existing literature regarding this condition.

A 3-year-old Indian boy, born at term to nonconsanguineous parentage, presented with high-grade fever for more than 1 month. He used to be irritable during the febrile period and frequented the bathroom to pour cold water over his body. A specific pattern of fever could be elicited – it appeared around 12 noon and resolved spontaneously after sundown. This pattern was noticed only during summer months. Interestingly, after the febrile hours, he used to be fine and playful. Weight gain was appropriate even during febrile period. On further review of history, the informant acknowledged that the child did not sweat even in the hot summer months, right from infancy. On physical examination, the skin was found to be dry (generalized in distribution without skip areas) but without any ichthyotic changes. Other ectodermal structures (hair, teeth, and nails) were unaffected. Family history was noncontributory. On systemic examination, there was no neurodeficit peripheral neuropathy and no murmur on evaluation of the cardiovascular system. Examination of higher mental function and intellectual development was as per age.

Routine workup of fever was not suggestive of any infective, inflammatory, or malignant cause. Considering clinical history and examination, a dermatological consultation was sought for further workup. In the dermatology clinic, colorimetric (starch–iodine) test failed to show any detectable perspiration (blue–black areas) anywhere. [Figure 1] Histopathological examination of skin biopsy, taken from the child's arm, revealed paucity of eccrine apparatus with few rudimentary sweat glands throughout the dermis and hypodermis along with sparse hair follicles. [Figure 2] Based on suggestive history, clinical examination, corroborative thermoregulatory sweat test, and histopathological findings, a diagnosis of CIGA was established. As per the recent Japanese guidelines,[1] he was graded as “severe” (score = 6) and subsequently started on tablet prednisolone (1 mg/day/kg) with gradual tapering. His parents were advised to limit his physical activities. However, no significant clinical improvement was evident even after 8 weeks of treatment. He remains on regular pediatric follow-up. We could not perform genetic study due to institutional limitations.

Figure 1

Starch–iodine test demonstrating complete absence of blue–black areas (some focal blue–black areas seen over the trunk, dorsa of feet, and knees was made by the attendant for proper positioning) (a and b)

Figure 2

Histopathology (hematoxylin and eosin stain) showing paucity of eccrine structures and hair follicles along with the absence of any inflammatory dermal aggregates (A, 40x); some rudimentary sweat glands in dermis (black arrows) (B, 100x); and normal eccrine coils in the reticular dermis and hypodermis (C, 100x)

Generalized anhidrosis occurs due to exogenous factors, dermatological diseases (primary), and neuropathic (secondary) causes. HED is one of the most common congenital cause of generalized anhidrosis in a child.[12] Since no ectodermal abnormality was found, the possibility of HED was unlikely. As the informant reported decreased perspiration since infancy, we attributed the diagnosis of generalized anhidrosis to be congenital. Although the exact pathophysiology of CIGA remains unknown, the absence of sweat gland or postsynaptic defect in the cholinergic receptors or secretory cells of eccrine glands may underlie the pathogenesis. Cevoli et al.[3] suggested a congenital ectodermal dysplasia that selectively affected the eccrine apparatus.

Sweat glands play an important role in overseeing the thermoregulatory control of the body. With their heat dissipating mechanisms being hampered, children are particularly more vulnerable because their core body temperature rises faster than adults. This culminates into elevated body temperature and the subsequent febrile response. On reviewing the literature in “PubMed” and “Medline” databases, we came across seven published cases of CIGA till date that we have duly summarized in Table 1.[3456]

Table 1

Clinical characteristics of the eight reported cases of CIGA#

Author (year)	Country	No^	Age* (years)	Sex	Family history]	History of consanguinity	Complaints	Mucocutaneous findings	Histopathology	Treatment
Mahloudji M et al. (1967)[4]	Iran	3	14612	MMF	All three affected were siblings; no other family members affected	Yes (parents were first cousins)	Inability to tolerate exposure to heat	Nil	Complete absence of sweat glands	Not mentioned
Frydman M et al. (1988) [5]	Israel	2	14 12	M F	They were siblings; no other family members affected	No	Heat intolerance and recurrent short bouts of fever	Abnormal palmar dermal ridges	Normal sweat gland and duct	Not mentioned
Cevoli S et al. (2002) [3]	Italy	1	45	F	Nil	No	Episodes of hyperthermia, photo- and phonophobia and migraine attack	Nil	Atrophy and morphologic changes of eccrine glands	Not mentioned
Shi G et al. (2021)[6]	China	1	43	M	Nil	No	Heat intolerance	Sparse axillary and beard hair	Complete absence of sweat gland in anhidrotic areas. Unaffected skin showed preserved sweat glands surrounded by S100 and PGP9.5 immunostaining	Not mentioned
Present case (2021)	India	1	3	M	Nil	No	Heat intolerance and recurrent bouts of fever	Nil	Sparse and some rudimentary sweat glands with paucity of hair follicles	General measures and oral prednisolone (1 mg/kg/day); no robust clinical improvement was noted after 8 weeks of therapy

*Age (years) refers to the age at presentation to the clinician ^ Number of cases in the report/case series. # Including the present case. Abbreviations: M=Male, F=Female

Systemic corticosteroids have been recommended in patients with acquired idiopathic generalized anhidrosis having severe symptoms that disrupt daily life or work. However, steroid resistance have been noted in patients with prolonged duration of anhidrosis.[1] Corticosteroids proved unsuccessful in our case. Cyclosporine works only in cases where peri-eccrine T-cell infiltrates are observed. Antihistamines may have a role by blocking the inhibitory action of histamine on acetylcholine-induced sweating.[26] As systemic medications provide variable results, emphasis should be on preventive measures. In this regard, care providers should maintain a cool environment (including installation of air-conditioners at home) for the patient and ensure lifestyle modifications like limitation of vigorous exercise and outdoor activities especially in the hot summer months and afternoon time). By adopting these simple measures, the serious complications of anhidrosis (heat cramps, exhaustion, and the dreaded heatstroke) may be averted.

The purpose of detailing this case is to familiarize clinicians with this uncommon condition, add to the literature on this rarely reported entity, and emphasize the need to consider disorders of anhidrosis as a potential cause of fever of unknown origin.

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Written informed consent obtained from the guardian.

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Conflicts of interest

There are no conflicts of interest.