That apparent normality did not last. During his four-week admission he suffered several further episodes of transient hypothermia accompanied by hypertension and sweating, each resolving spontaneously. Over the following four years he was admitted more than a dozen times with the same constellation of symptoms: hypothermia plunging as low as 28 degrees Celsius, profuse diaphoresis, blood pressure disturbance that swung between severe hypertension and profound hypotension, and symptomatic hyponatremia with sodium levels between 119 and 132 mmol/L. On every occasion, repeat testing found no evidence of infection or endocrine disease. This pattern of periodic hypothermia, autonomic instability and low sodium pushed the clinical team toward an entirely different explanation: a thermoregulatory disorder originating in the central nervous system. When the authors re-examined his prior brain imaging, they found something the original report had missed, an abnormality of the corpus callosum together with a cavum veli interpositi, a fluid-filled structure that can accompany callosal malformations.

Those findings were supportive of a diagnosis of Shapiro syndrome, an extraordinarily rare condition first described in 1969 by Shapiro, Williams and Plum in two patients who presented with spontaneous episodic hypothermia and hyperhidrosis alongside radiographic evidence of agenesis of the corpus callosum. The corpus callosum is the thick bundle of nerve fibres connecting the brain’s two hemispheres, and its absence or malformation is the structural hallmark of the syndrome. Since the original description, the recognised phenotype has expanded to include other autonomic disturbances such as hypertension or hypotension, altered consciousness and metabolic derangement. Of the approximately 60 cases reported in the literature, about half had no evidence of callosal dysgenesis at all; these are considered a variant of the syndrome, sometimes called episodic spontaneous hypothermia, and they tend to affect older patients.

Understanding why such a syndrome can exist requires understanding how tightly the human body normally controls its temperature. The evolution of mammals from aquatic to terrestrial life posed a serious thermoregulatory challenge, because land temperatures vary far more than water temperatures. That pressure drove a transition from poikilothermy, in which body temperature drifts with the environment, to homeothermy, the ability to hold internal temperature within a narrow set range. Holding a high, stable temperature maximises enzymatic activity, speeds neural processing and improves healing. Endothermy, the generation of internal heat, gave early mammals a survival edge over ectothermic dinosaurs, which depended on external heat sources, were inactive at night, were more vulnerable to seasonal change and were in some cases restricted to particular latitudes.

In humans, the hypothalamus acts as the thermostat. The pre-optic area of the anterior hypothalamus is chiefly responsible for temperature control, integrating thermal signals arriving from skin and visceral thermoreceptors with direct measurements of hypothalamic temperature. Within this region, distinct populations of neurons perform complementary roles. Warm-sensing neurons increase their activity in response to heat and receive excitatory input from peripheral warm receptors; when they fire, they trigger heat-loss mechanisms such as sweating and peripheral vasodilation. Cold-sensing neurons make up less than 5 percent of the pre-optic population and are normally held in check by tonic inhibition from warm-sensing neurons, balanced against tonic excitation from temperature-insensitive neurons. When that inhibition is lifted, cold-defence mechanisms activate: shivering and non-shivering thermogenesis, peripheral vasoconstriction, activation of brown fat through sympathetic excitation, hypothalamic-pituitary stimulation of thyroxine production to raise basal metabolic rate, and even behavioural responses like huddling. Infection complicates this picture because endogenous pyrogens suppress warm-sensing neurons, raising the set point and producing fever.

Hypothermia itself is defined as a core temperature below 35 degrees Celsius and is graded as mild, between 32 and 35 degrees, moderate, between 28 and 32 degrees, or severe, below 28 degrees. The physiological consequences scale with severity. At the cellular level, cold drives water crystallisation, membrane disruption and protein changes, while secondary ischaemic injury follows vasoconstriction, endothelial damage and thrombosis. Mild hypothermia typically produces a catecholamine surge with tachycardia and hypertension, which may explain the striking blood pressure of 207/176 mmHg in the case described here. As temperature falls further, cardiovascular function degrades into progressive bradycardia and hypotension. Cerebral metabolic rate drops by roughly 6 percent for every 1-degree Celsius decline, producing confusion, behavioural change, ataxia and progressive obtundation. Respiratory drive is depressed, causing respiratory acidosis, while cold diuresis, impaired renal tubular function and occasional shivering-induced rhabdomyolysis disturb electrolytes, a mechanism relevant to the patient’s recurrent hyponatremia. Coagulopathy from platelet and clotting-factor dysfunction is also common.

Because so many conditions can lower body temperature, clinicians must work through a broad differential. Exogenous hypothermia from environmental exposure is compounded by age, intoxication, homelessness, low body fat and immobility. Endogenous causes include sepsis, especially gram-negative bacteraemia, hypovolaemic shock, hypoglycaemia, diabetic ketoacidosis, uremia and hepatic encephalopathy, and endocrinopathies such as hypothyroidism, adrenal failure and hypopituitarism. Drugs matter too: alcohol, opioids, barbiturates and phenothiazines impair thermal perception and cause vasodilation, while at the opposite extreme, neuroleptic malignant syndrome, serotonin syndrome and malignant hyperthermia produce dangerous overheating. Neurological causes form their own category. Peripheral neuropathies rarely cause overt thermoregulatory failure except in rare genetic disorders such as congenital insensitivity to pain with anhidrosis. Spinal cord injuries, particularly high cervical lesions, impair both afferent temperature sensing and efferent responses like shivering and vasomotor control. Focal lesions of the hypothalamus or brainstem, demyelinating disease, autoimmune encephalitis and neurodegenerative conditions such as Parkinson’s disease can all disrupt central temperature control, and episodic hypothermia has been documented in migraine, HIV, Parkinson disease and multiple sclerosis.

The authors argue that a central thermoregulatory disorder should be suspected whenever a patient presents with unexplained hypothermia or hyperthermia, particularly without environmental triggers, infection, endocrinopathy or organ failure. It remains largely a diagnosis of exclusion. Additional neurological signs such as autonomic dysfunction or altered mental status may point toward a central cause, though they can also result directly from the thermal derangement itself. Structural brain imaging is paramount in such cases, precisely because the decisive clue in this patient, callosal dysgenesis with a cavum veli interpositi, was present on an earlier scan but initially overlooked. The case is a striking reminder that radiological findings can hide in plain sight until the clinical pattern demands a second look.

Why the corpus callosum matters in Shapiro syndrome is still unresolved, and dysgenesis alone is clearly insufficient to cause the disorder. Hypothalamic involvement is supported by findings of hypothalamic neuronal loss in some reported cases, although structural imaging is often normal. Shapiro’s original hypothesis of diencephalic epilepsy has not held up: patients rarely show EEG abnormalities and generally do not respond to anticonvulsants. Alternative mechanisms, including neurotransmitter dysfunction and hypermelatoninemia, have been proposed, but the cause-and-effect relationship is difficult to disentangle. Some support for the neurotransmitter hypothesis comes from occasional responses to prophylactic agents such as clonidine, clomipramine and cyproheptadine. The patient in this report briefly received clonidine, but treatment was not continued because of poor response, non-compliance and episodes of hypotension, underscoring how difficult management can be in a condition whose mechanisms remain obscure.

The broader lesson from this case extends beyond one rare syndrome. Virtually any neurological disease affecting cognition, sensation or movement can increase susceptibility to thermal dysregulation, but periodic hypothermia and hyperthermia should prompt consideration of a central disorder once infection and systemic disease have been excluded. Diagnostic precision matters because treatment strategies, both pharmacological and non-pharmacological, differ according to the underlying cause, and misattributing recurrent hypothermia to infection leads to repeated courses of unnecessary antimicrobials, as happened here before the true diagnosis emerged. For a man whose body temperature repeatedly fell to levels that would kill most people within hours, the answer lay not in his blood but in a structure of his brain that no one had looked at carefully enough, until a decade of mysterious admissions finally forced a second reading of the scan.

Subject of Research: Shapiro syndrome, a rare disorder of central thermoregulation associated with agenesis of the corpus callosum

Article Title: Recurrent Hypothermia and Autonomic Dysfunction Secondary to Shapiro Syndrome

Article References: Kumar, N., Johnson, J., Watkins, S., & Mulroy, E. (2026). Recurrent Hypothermia and Autonomic Dysfunction Secondary to Shapiro Syndrome. Annals of Clinical and Translational Neurology, 13(8), 1719-1725. https://doi.org/10.1002/acn3.70419

Image Credits: AI Generated

DOI: 10.1002/acn3.70419

Keywords: Shapiro syndrome, hypothermia, corpus callosum, hypothalamus, thermoregulation, autonomic dysfunction, hyperhidrosis, hyponatremia, neurology, case report, episodic spontaneous hypothermia, diencephalon