Abstract
Cushing’s syndrome in early childhood is rare and may be particularly challenging to diagnose when adrenal imaging is unrevealing. We report the case of a 23-month-old girl who presented with rapid weight gain, cushingoid appearance, hypertrichosis, severe hypertension, irritability, and developmental regression. Biochemical assessment confirmed adrenocorticotropic hormone (ACTH)-independent hypercortisolism, with suppressed ACTH, loss of circadian cortisol rhythm, lack of cortisol suppression following dexamethasone administration, and increased 24-hour urinary free cortisol excretion. Adrenal magnetic resonance imaging showed morphologically normal adrenal glands. Adrenal computed tomography was not performed, to avoid additional ionising radiation after a non-diagnostic adrenal MRI in a 23-month-old child. Adrenal scintigraphy with ¹³¹I-NP-59 after metyrapone-induced suppression demonstrated bilateral adrenal uptake, slightly more prominent on the right. The patient underwent right adrenalectomy. Histopathological examination showed micronodular adrenocortical hyperplasia without pigmentation, atypia, or malignant features, consistent with isolated micronodular adrenal disease. Following surgery, blood pressure, metabolic abnormalities, cutaneous manifestations, and motor function improved markedly. Steroid supplementation was required for only 3 days post-operatively, with no evidence of persistent adrenal insufficiency. At 3 years of follow-up, there were no clinical features of recurrent hypercortisolism, blood pressure remained normal without antihypertensive therapy, body mass index had markedly improved, and available biochemical parameters were reassuring. This case highlights that isolated micronodular adrenal disease should be considered in very young children with ACTH-independent Cushing’s syndrome even when adrenal magnetic resonance imaging is normal. Functional adrenal imaging may be useful in selected cases, and unilateral adrenalectomy may achieve durable remission while delaying permanent adrenal insufficiency.
Introduction
Cushing’s syndrome (CS) is a multisystem disorder caused by chronic exposure to excess glucocorticoids. In paediatric patients, the earliest and most reliable manifestations of hypercortisolism are excessive weight gain and impaired linear growth, often accompanied by central adiposity, moon facies, metabolic abnormalities, and neurobehavioural symptoms (–). Hypertension, dyslipidaemia, insulin resistance, and psychological or developmental changes may all occur and should raise suspicion of endogenous hypercortisolism (, –).
The diagnostic approach to CS requires biochemical confirmation of cortisol excess, distinction between ACTH-dependent and ACTH-independent forms, and localisation of the source of cortisol overproduction (, , , ). In younger children, ACTH-independent forms are proportionally more frequent than in adolescence and include adrenal adenomas, adrenocortical carcinoma, and different forms of adrenal hyperplasia (–).
Adrenocortical hyperplasia comprises several distinct entities. Bilateral forms include primary bilateral macronodular adrenocortical hyperplasia (PBMAH) and micronodular adrenal disease, the latter including primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenal disease (iMAD) (, –). Micronodular forms are particularly relevant in childhood, whereas macronodular forms tend to predominate in adulthood (–). Most cases are associated with dysregulation of the cyclic AMP/protein kinase A signalling pathway, although the underlying genetic basis remains unresolved in many patients (–).
iMAD is characterised histologically by bilateral, multiple, non-pigmented adrenocortical micronodules, usually measuring less than 1 cm. Unlike PPNAD, the characteristic lipofuscin pigmentation and internodular cortical atrophy are absent (, –). Childhood-onset CS carries substantial morbidity, resulting both from the direct effects of hypercortisolism and from treatment-related consequences (, –).
We report the case of a 23-month-old girl with ACTH-independent CS caused by iMAD, presenting with severe obesity, malignant hypertension, and developmental regression. Despite normal adrenal MRI and bilateral functional uptake on scintigraphy, sustained clinical remission was achieved following unilateral adrenalectomy. The novelty of this report lies in the very young age at presentation, the use of functional adrenal imaging to support decision-making when conventional imaging was unrevealing, and the successful steroid-sparing initial surgical approach.
Case report
A 23-month-old girl was brought to the emergency department because of marked irritability, frequent crying, insomnia, and major behavioural change. Her mother reported rapid and significant weight gain, acne, and excessive body hair over the preceding 4 to 5 months (Figure 1).
Figure 1
She was born from a diamniotic dichorionic twin pregnancy complicated by intrauterine growth restriction affecting both foetuses. Delivery was by caesarean section at 36 weeks’ gestation because of abnormal placental blood flow. Apgar scores were 8, 9, and 10 at 1, 5, and 10 minutes, respectively, and birth weight was 2360 g (-0.61 SDS), between the 10th and 50th percentiles on the Fenton chart.
Until 18 months of age, her growth pattern, psychomotor development, and eating behaviour were reported to be similar to those of her twin sister. Thereafter, progressive motor regression became evident, with lower limb hypotonia and reluctance to walk despite previous independent ambulation, together with a marked decline in her already limited verbal abilities. Routine primary care follow-up had been interrupted between 4 and 22 months of age because of adverse social circumstances; the available opportunistic measurements nevertheless suggested rapid weight acceleration with relatively preserved but non-accelerating linear growth. This longitudinal pattern is illustrated in Figure 2.
Figure 2
The family history included second-degree parental consanguinity. The family context was marked by social vulnerability, including economic hardship, low maternal educational attainment, single-parent caregiving, and interruption of routine primary care follow-up.
On admission, the child had marked central adiposity, dorsocervical fat accumulation, cushingoid facies, cervical acanthosis nigricans, facial acne, and facial and dorsal hypertrichosis (Figure 1). Mild striae rubrae were present. There were no signs of virilisation. Sparse axillary and pubic hair were noted, together with lipomastia (Tanner stage A2B1P2). She was extremely irritable, with recurrent paroxysms of crying.
Blood pressure was severely elevated at 190/160 mmHg, well above the 95th percentile for age and sex. Weight was 20.25 kg (+4.75 SDS), height 84 cm (-0.38 SDS), and body mass index (BMI) 28.7 kg/m² (+7.36 SDS), indicating severe obesity. The marked dissociation between weight (+4.75 SDS) and height (-0.38 SDS) was consistent with the growth pattern characteristic of endogenous hypercortisolism, in which weight gain is disproportionate to linear growth.
Biochemical investigation confirmed ACTH-independent hypercortisolism. ACTH was suppressed (<5 pg/mL), the normal circadian cortisol rhythm was lost (00:00, 35.9 µg/dL; 05:00, 42.0 µg/dL; 08:00, 32.5 µg/dL), and there was no suppression following overnight dexamethasone administration (0.3 mg/m²; 08:00 cortisol 33.11 µg/dL). Twenty-four-hour urinary free cortisol (UFC) excretion was markedly elevated at 462.6 µg/24 h (reference range 28.5–213.7 µg/24 h).
Urinary metanephrines, thyroid-stimulating hormone, free thyroxine, insulin-like growth factor 1, luteinising hormone, follicle-stimulating hormone, total testosterone, and 17-hydroxyprogesterone were within normal limits. Aldosterone and renin concentrations were reduced. Metabolic evaluation demonstrated dyslipidaemia and insulin resistance without diabetes mellitus: total cholesterol 223 mg/dL, HDL cholesterol 63 mg/dL, LDL cholesterol 154 mg/dL, triglycerides 160 mg/dL, HOMA-IR 5.7, and HbA1c 4.8%. Severe vitamin D deficiency was present, with a 25-hydroxyvitamin D level of 6.9 ng/mL. A skeletal survey, assessing the axial and appendicular skeleton rather than a single symptomatic region, was performed in the context of severe hypercortisolism and profound vitamin D deficiency to assess generalised bone demineralisation and exclude fragility fractures.
Assessment for hypertensive target-organ damage showed concentric left ventricular hypertrophy with preserved systolic function, without evidence of retinopathy or albuminuria.
Adrenal MRI revealed morphologically normal adrenal glands, with no hypertrophy, focal lesion, or retroperitoneal abnormality. Adrenal CT was not performed, in order to avoid additional ionising radiation in a 23-month-old child after a non-diagnostic adrenal MRI. Given the clear biochemical evidence of ACTH-independent hypercortisolism and the non-diagnostic anatomical imaging, functional adrenal imaging was selected to assess adrenal activity and support surgical planning.
Cranial computed tomography excluded an intracranial mass but demonstrated non-specific leukoencephalopathy and cortical-subcortical atrophy. MRI of the hypothalamic-pituitary region showed normal anatomy. However, T2-weighted brain imaging demonstrated hyperintense lesions involving the periventricular, frontoparietal, and temporal subcortical white matter, globus pallidus, and pons, with diffusion restriction. The aetiology of these findings remained uncertain. Although hypercortisolism may have contributed to cerebral atrophy, behavioural change, and neuromotor deterioration, the extent of the neuroradiological abnormalities raised additional diagnostic considerations, including an underlying metabolic or genetic disorder. Marked diffuse cerebral and cerebellar cortical atrophy was also present.
Adrenal scintigraphy with ¹³¹I-NP-59 was performed after one week of metyrapone-induced adrenal suppression to localise the source of cortisol excess (, ). Sequential thoraco-abdominal-pelvic imaging on days 0, 3, 5, and 7 after intravenous administration of 19.7 MBq of ¹³¹I-NP-59 showed bilateral adrenal uptake, slightly more pronounced and irregular on the right. Uptake indices on days 3, 5, and 7 were 0.55%, 0.71%, and 0.69% of the injected dose in the right adrenal gland and 0.53%, 0.67%, and 0.63% in the left adrenal gland (Figure 3).
Figure 3
Hypertension was initially difficult to control and required combination therapy with an angiotensin-converting enzyme inhibitor (enalapril 0.6 mg/kg/day), beta-blocker (propranolol 1.5 mg/kg/day), calcium-channel blocker (amlodipine 0.2 mg/kg/day), and diuretics (furosemide 1.5 mg/kg/day and spironolactone 1.1 mg/kg/day).
Although scintigraphy demonstrated bilateral adrenal hyperfunction, uptake was slightly more prominent on the right. Given the patient’s very young age, the aim of preserving endogenous adrenal function, and the possibility of achieving disease control with a steroid-sparing approach, right adrenalectomy was selected as the initial therapeutic strategy (, , ).
Following surgery, the patient received steroid supplementation for only 3 days, with no clinical or biochemical evidence of persistent adrenal insufficiency. Blood pressure improved rapidly, allowing progressive reduction of antihypertensive therapy. Macroscopically, the resected right adrenal gland measured 3.6 × 2.5 × 0.5 cm and had a homogeneous yellow appearance. Six nodular lesions measuring 0.5–1.2 cm were identified. Histopathological examination showed micronodular adrenocortical hyperplasia without pigmentation, atypia, or malignant features, consistent with iMAD (Figure 4).
Figure 4
Thirteen days after surgery, biochemical and metabolic parameters had already improved substantially. Serum cortisol was 7.90 µg/dL, ACTH 6.00 pg/mL, HOMA-IR 1.6, total cholesterol 141 mg/dL, LDL cholesterol 72 mg/dL, and triglycerides 132 mg/dL (Table 1). Blood pressure had fallen to below the 90th percentile despite a reduced antihypertensive regimen, and the cutaneous manifestations of hypercortisolism had visibly regressed.
Table 1
| Parameter | At presentation | 13 days post-op | 3-year follow-up | Reference values/comments |
|---|---|---|---|---|
| Age | 23 months | — | Approximately 5 years | — |
| Blood pressure | 190/160 mmHg | <90th percentile on reduced treatment | <90th percentile off treatment | Percentiles adjusted for age, sex and height |
| Weight | 20.25 kg (+4.75 SDS) | — | 19.4 kg (+0.36 SDS) | SDS reported for age and sex |
| Height | 84 cm (-0.38 SDS) | — | 105.5 cm (-0.51 SDS) | SDS reported for age and sex |
| BMI | 28.7 kg/m² (+7.36 SDS) | — | 17.43 kg/m² (+1.20 SDS) | Marked post-operative improvement |
| Bone age | — | — | Appropriate for chronological age | — |
| ACTH | <5 pg/mL | 6.00 pg/mL | 17.1 pg/mL | 7.2 to 63.3 pg/mL |
| Serum cortisol | 32.5–42.0 µg/dL¹ | 7.90 µg/dL | 3.81 µg/dL | 5–25 µg/dL² |
| Post-dexamethasone cortisol | 33.11 µg/dL³ | — | — | <1.8 µg/dL |
| 24-hour urinary free cortisol | 462.6 µg/24 h | Not available | Not available | 28.5–213.7 µg/24 h; serial post-op UFC not available |
| Total cholesterol | 223 mg/dL | 141 mg/dL | Normal | <170 mg/dL |
| HDL cholesterol | 63 mg/dL | — | Normal | >45 mg/dL |
| LDL cholesterol | 154 mg/dL | 72 mg/dL | Normal | <110 mg/dL |
| Triglycerides | 160 mg/dL | 132 mg/dL | Normal | <150 mg/dL |
| HbA1c | 4.8% | — | Normal | No diabetes mellitus |
| HOMA-IR | 5.7 | 1.6 | 0.69 | Improved insulin resistance |
| 25-hydroxyvitamin D | 6.9 ng/mL | — | — | Severe deficiency at presentation |
| Aldosterone | 4.1 ng/dL | 2.9 ng/dL | 1.22 ng/dL | 7–93 ng/dL |
| Active renin | 8.3 µIU/mL | — | — | 21.1–93.1 µIU/mL |
Summary of relevant auxological, clinical, biochemical and hormonal investigations at presentation, 13 days post-operatively, and at 3-year follow-up.
¹Range across circadian cortisol profile (00:00–08:00 h), reflecting loss of diurnal rhythm.
²Interpretation should consider timing of sampling and post-operative context.
³Post-overnight dexamethasone administration (0.3 mg/m²), 08:00 cortisol, confirming lack of suppression.
ACTH, adrenocorticotropic hormone; BMI, body mass index; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; LDL, low-density lipoprotein; SDS, standard deviation score; UFC, urinary free cortisol; —, not measured/not applicable at this time point.
Further genetic and metabolic investigations were undertaken to exclude syndromic causes of both hypercortisolism and the marked neuroradiological abnormalities. Because of parental consanguinity, the possibility of an autosomal recessive condition was specifically considered. Genetic investigation comprised a clinical mendeliome, an NGS-based analysis of disease-associated genes. It identified three variants of uncertain significance in genes associated with autosomal dominant inheritance patterns; no conclusive molecular diagnosis, including no explanatory recessive diagnosis, was established. The complementary metabolic work-up was also non-diagnostic.
At 3 years of follow-up, the child had no clinical features suggestive of recurrent hypercortisolism. Weight had normalised at 19.4 kg (+0.36 SDS) and BMI had fallen to 17.43 kg/m² (+1.20 SDS), with marked improvement in body composition. Height was 105.5 cm (-0.51 SDS), remaining within the normal range, and bone age was appropriate for chronological age, consistent with restoration of normal linear growth velocity following disease remission. Available biochemical findings remained favourable, with morning cortisol 3.81 µg/dL, ACTH 17.1 pg/mL, HOMA-IR 0.69, and normal glycaemic and lipid profiles. Thyroid function and androgen profile remained normal. All antihypertensive therapy was discontinued, with blood pressure remaining below the 90th percentile for age, sex, and height. Motor function also improved substantially.
Post-operative follow-up was based on serial clinical assessment, including growth, BMI, blood pressure, cutaneous features, and neuromotor recovery, together with available serum cortisol, ACTH, and metabolic parameters. Serial post-operative 24-hour UFC measurements were not available, which limits the biochemical documentation of remission. Long-term surveillance has therefore been reinforced and should include periodic UFC assessment whenever feasible, in addition to clinical evaluation and serum markers. A clinical timeline is provided in Figure 5.
Figure 5
Discussion
This case illustrates several important diagnostic and therapeutic challenges in paediatric ACTH-independent CS.
First, it highlights the need for a high index of suspicion when a very young child presents with rapid weight gain, cushingoid appearance, severe hypertension, and developmental regression. In paediatric practice, excessive weight gain associated with impaired linear growth or an altered growth trajectory is particularly suggestive of endogenous hypercortisolism (, –). In the present case, the dissociation between marked weight gain and non-accelerating linear growth was a key clinical clue.
Second, this case emphasises the diagnostic difficulty of micronodular adrenal disease. Biochemical findings clearly indicated ACTH-independent hypercortisolism, yet adrenal MRI was entirely normal. This is consistent with previous reports showing that iMAD may be missed on conventional cross-sectional imaging, particularly when nodules are very small (, –). Adrenal CT was not pursued because MRI had already shown morphologically normal glands and because additional ionising radiation was considered undesirable in a 23-month-old child. Definitive diagnosis therefore depended on histopathological examination of the resected adrenal gland.
The pathological findings supported the diagnosis of iMAD rather than PPNAD, as the nodules were non-pigmented and there was no evidence of the lipofuscin deposition or internodular cortical atrophy classically seen in PPNAD (, –). This distinction is clinically relevant because PPNAD is much more strongly associated with Carney complex and PRKAR1A-related disease (–).
A further notable aspect was the value of functional imaging. ¹³¹I-NP-59 scintigraphy demonstrated bilateral adrenal uptake despite morphologically normal adrenal glands on MRI, thereby supporting bilateral adrenal hyperfunction when anatomical imaging was unrevealing (, ). It also provided evidence of slight right-sided predominance, which contributed to the decision to pursue right unilateral adrenalectomy. This case underlines the technical challenges of performing adrenal scintigraphy in very young children, particularly in the absence of widely standardised paediatric protocols for adrenal suppression and thyroid blockade.
The severe developmental regression and marked neuroradiological abnormalities considerably broadened the differential diagnosis. Hypercortisolism may contribute to cerebral atrophy, behavioural change, and neuromotor deterioration, but white-matter lesions with diffusion restriction are not typical findings of CS and therefore justified extended genetic and metabolic investigation. Although these investigations were inconclusive, the substantial clinical improvement after treatment suggests that cortisol excess played an important pathogenic role in the child’s presentation. No follow-up neuroimaging was performed; therefore, the evolution of the neuroradiological abnormalities remains unknown, which represents a limitation of this report.
From a genetic perspective, parental consanguinity raised the possibility of an autosomal recessive disorder, particularly in the setting of neurological abnormalities. However, clinical mendeliome analysis did not identify a conclusive molecular diagnosis. The molecular basis of iMAD remains incompletely understood. In contrast to PPNAD, which is strongly associated with germline PRKAR1A pathogenic variants, most reported cases of iMAD appear sporadic (–). Genetic abnormalities commonly implicated in PBMAH, such as ARMC5 variants, and activating alterations in GNAS have generally not been identified in iMAD (–). Further genomic studies are needed to clarify the pathogenesis of this rare disorder.
An especially relevant feature of this case is the successful use of unilateral adrenalectomy despite evidence of bilateral adrenal activity on scintigraphy. Bilateral adrenalectomy is highly effective in controlling hypercortisolism but commits the patient to lifelong adrenal replacement therapy and exposes them to the risk of adrenal crisis. In our patient, the slight predominance of right-sided uptake, together with her very young age and the wish to preserve endogenous adrenal function, supported unilateral adrenalectomy as a cautious initial strategy (, , ). The sustained clinical remission observed over 3 years suggests that this may be a reasonable option in selected paediatric cases, although prolonged follow-up remains essential because recurrence is still possible.
Post-operative surveillance after unilateral adrenalectomy should not rely on serum cortisol and ACTH alone. Serial clinical assessment is essential, but biochemical monitoring for recurrence should include 24-hour UFC whenever feasible, complemented by other markers such as late-night salivary or serum cortisol and dexamethasone suppression testing according to age, feasibility, and local practice (, , ). In the present case, serial post-operative UFC measurements were not available; this limits the biochemical confirmation of long-term remission and has been explicitly recognised as a limitation.
The novelty of this report is therefore threefold: iMAD was diagnosed in a very young child despite normal adrenal MRI; functional adrenal imaging was used to support localisation and surgical planning in the context of non-diagnostic anatomical imaging; and unilateral adrenalectomy achieved a 3-year clinical remission without persistent adrenal insufficiency, despite bilateral adrenal uptake.
Conclusion
Isolated micronodular adrenal disease should be considered in very young children with ACTH-independent CS even when adrenal MRI is normal. Functional imaging may provide useful localisation data when anatomical imaging is unrevealing. In carefully selected patients, unilateral adrenalectomy may achieve durable clinical remission while delaying permanent adrenal insufficiency, but prolonged clinical and biochemical surveillance, including periodic UFC assessment whenever feasible, remains essential.
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Author contributions
MV: Writing – original draft. GC: Writing – review & editing. JS: Writing – original draft. PF: Writing – review & editing. DC: Writing – review & editing. MK: Writing – review & editing. JG: Conceptualization, Writing – original draft.
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Summary
Keywords
ACTH-independent hypercortisolism, adrenal scintigraphy, isolated micronodular adrenal disease, paediatric Cushing’s syndrome, severe hypertension, unilateral adrenalectomy
Citation
Valério M, Croca GP, Simões J, Ferreira P, Costa DC, Knoblich M and Galhardo J (2026) Case Report: ACTH-independent Cushing’s syndrome caused by isolated micronodular adrenal disease in a 23-month-old girl. Front. Endocrinol. 17:1863025. doi: 10.3389/fendo.2026.1863025
Received
22 April 2026
Revised
16 June 2026
Accepted
24 June 2026
Published
21 July 2026
Volume
17 - 2026
Edited by
Nicola Improda, AORN Santobono-Pausilipon, Italy
Reviewed by
Laura Chioma, Bambino Gesù Childrens’ Hospital, Italy
Rosanna Masturzo, Universita degli Studi di Salerno - Campus Baronissi, Italy
Updates
Copyright
© 2026 Valério, Croca, Simões, Ferreira, Costa, Knoblich and Galhardo.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Marta Valério, valerio.marta@gmail.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.