An unusual presentation of familial glucocorticoid deficiency type 2 with tall stature: A case report

INTRODUCTION

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated cortisol deficiency in the presence of preserved mineralocorticoid secretion. It results from mutations affecting the adrenocorticotropic hormone (ACTH) signaling pathway, most commonly in the melanocortin 2 receptor (MC2R; FGD type 1) and melanocortin 2 receptor accessory protein (MRAP; FGD type 2) genes.^[1,2]

The disorder typically manifests in infancy or early childhood with hyperpigmentation, hypoglycemia, recurrent infections, seizures, and failure to thrive, but without the salt-wasting seen in primary adrenal failure.^[2-4] The overall prevalence is unknown, but an increasing number of cases are reported, as genetic diagnostics have become more accessible.^[2,3]

FGD type 2 (FGD2) specifically results from MRAP mutations, which impair ACTH receptor trafficking and signaling, leading to cortisol deficiency despite intact mineralocorticoid activity.^[1]

While tall stature is a common feature of FGD type 1 (FGD1), patients with FGD2 often present earlier and tend to have a normal height standard deviation (SD) score at diagnosis.^[3]

The prevalence of FGD is unknown, but more cases are being identified as next-generation sequencing (NGS) becomes available. Beyond MC2R and MRAP, additional genes (NNT, STAR, MCM4, TXNRD2, and SGPL1) have been implicated, expanding the genetic spectrum of FGD.^[5,6]

Here, we report a case of a genetically confirmed FGD2 in a young male, emphasizing diagnostic challenges, genotype-phenotype correlations, and the impact of timely glucocorticoid replacement.

CASE REPORT

A 2-year-2-month-old male child, the second born of nonconsanguineous parents, presented with recurrent infections since infancy. The family history was significant; an elder sibling had died at 19 months of age with similar complaints, raising suspicion of a heritable disorder.

DISCUSSION

FGD2 is an uncommon cause of primary adrenal insufficiency in children and remains a diagnostic challenge due to its rarity and overlapping phenotype with other forms of adrenal disease. The cardinal clinical manifestations include generalized hyperpigmentation, recurrent symptomatic hypoglycemia, and increased susceptibility to infections, usually in the setting of preserved mineralocorticoid function. Our patient’s presentation was consistent with these features, although tall stature was unusual and raised important diagnostic considerations.

The absence of salt-wasting, dehydration, or electrolyte disturbances in our patient indicated intact aldosterone function, which is typical of FGD and distinguishes it from other forms of primary adrenal insufficiency, such as 21-hydroxylase deficiency-related CAH, which was considered but rendered highly unlikely by the nearly undetectable 17OHP levels. These findings support the integrity of the mineralocorticoid axis, consistent with previous descriptions of FGD2. The common differential diagnosis of primary adrenal insufficiency in children is summarized in Table 2.

Tall stature is typically associated with FGD1, caused by mutations in the MC2R gene; it may occasionally occur in FGD2 as well. The proposed mechanisms include chronic ACTH hypersecretion, leading to increased melanocortin pathway activation, secondary stimulation of the growth hormone axis, or individual variability in the onset and duration of cortisol deficiency. Our case adds to this small subset of FGD2 presentations with tall stature, as highlighted by Chung et al. and Elias et al.^[2,3] In the largest comparative cohort study to date, Chung et al. described the phenotypic differences between FGD1 and FGD2, demonstrating that children with MC2R mutations (FGD1) often exhibit a significant increase in height SD scores (+ 1.75 ± 1.53), whereas those with MRAP mutations (FGD2) usually present earlier in life with normal stature (+ 0.12 ± 1.35) for age (P < 0.01). The median age of onset in the FGD2 group (0.08 years) fell within the neonatal period, highlighting the more severe, earlier presentation of this subtype. This distinction has been emphasized to assist clinicians in suspecting FGD subtype based on clinical features, although overlap can occur in practice, and tall stature should not exclude FGD2 as a diagnostic possibility.^[2,3]

Hyperpigmentation remains the most consistent finding in FGD2. It is driven by chronic elevation of ACTH, which cross-reacts with melanocortin-1 receptors in the skin, resulting in diffuse pigmentation from birth or early infancy. This was also seen in the Chinese Han neonate reported by Chen et al., who presented at only a few weeks of age with generalized hyperpigmentation, severe hypoglycemia, and recurrent infections.^[4] Genetic analysis confirmed a homozygous splice-site mutation in MRAP, establishing the diagnosis of FGD2. Importantly, hydrocortisone replacement resulted in clear clinical improvement, including regression of pigmentation and stabilization of blood glucose levels, underscoring the reversible nature of these clinical features once treatment is initiated.^[4]

Hypoglycemia is another hallmark of FGD2 and is often severe enough to result in seizures or even permanent neurological damage if diagnosis is delayed. A case from Turkey, described by Akin et al., involved an infant who experienced recurrent hypoglycemic convulsions before glucocorticoid deficiency was recognized. Following the introduction of hydrocortisone, seizure episodes resolved, and developmental milestones were attained appropriately.^[7] This observation reinforces the critical importance of timely intervention in preventing long-term complications. Recurrent infections, as observed in both the Chinese and Turkish reports, highlight the systemic impact of cortisol deficiency on stress response and immune regulation.

The genetic basis of FGD2 has also been refined in recent years. In 2005, Metherell et al. first established MRAP as a critical partner for ACTH receptor trafficking, and subsequent studies have identified a growing spectrum of pathogenic variants.^[1,8] A recent report from China described both novel MC2R mutations and previously known MRAP variants in three children with glucocorticoid deficiency, showing that the disorder spans both new and recurrent genetic events and is not confined to any single population.^[9] The MRAP splice-site mutation identified (c.106+1G>A) results in predicted loss of exon-intron boundary integrity, leading to truncated MRAP protein and impaired ACTH receptor trafficking. Although no genotypephenotype correlation has been established linking MRAP variants to growth abnormalities, such cases warrant further study through bioinformatics and functional assays.

The clinical utility of genetic confirmation extends beyond establishing diagnosis. For families, it provides recurrence risk estimates and enables carrier detection in parents and siblings. In the Chinese neonate with an MRAP splice mutation, family analysis confirmed heterozygosity in both parents and the maternal grandmother, permitting precise counseling about future pregnancies.^[4] For clinicians, genetic confirmation also helps exclude common mimics such as CAH, which was biochemically improbable in our patient, and guides lifelong follow-up with an emphasis on glucocorticoid rather than mineralocorticoid replacement.

Treatment outcomes described in the literature consistently highlight the reversibility of many features once glucocorticoid replacement is introduced. Hyperpigmentation lightens gradually, hypoglycemia resolves, and infection susceptibility decreases when cortisol physiology is restored.^[4,7] In the Turkish case, seizure frequency decreased, and neurodevelopment remained age-appropriate after initiation of hydrocortisone.^[7] In the Chinese neonate, pigmentation regressed, and hypoglycemic crisis abated within months of therapy.^[4] Hydrocortisone replacement leads to rapid clinical recovery, fading pigmentation, resolution of hypoglycemia, and decreased infection susceptibility. Our patient’s 1-year follow-up supports this observation, underscoring the importance of early recognition and lifelong adherence to therapy. These cases show that while the genetic defect is permanent, timely intervention can greatly improve clinical outcomes. On the other hand, delays in therapy carry a well-documented risk of irreversible brain injury from recurrent hypoglycemia or sudden adrenal crisis.^[2,4,7]

The broader clinical implication is that FGD2 must remain in the differential diagnosis for any child presenting with hyperpigmentation and unexplained recurrent hypoglycemia, even in the absence of electrolyte abnormalities. While tall stature is not typical of FGD2, its presence should not preclude consideration of the diagnosis. Rather, it may reflect individual variability or prolonged, untreated cortisol deficiency. As genetic testing becomes widely available, physicians should use it early in suspected cases, as it not only confirms the diagnosis but also directs management and family planning.

CONCLUSION

FGD2 should be suspected in children presenting with hyperpigmentation, recurrent hypoglycemia, and infections, even when stature/height is normal. Confirmation through MRAP gene testing ensures diagnostic accuracy and enables family counseling. Timely glucocorticoid replacement prevents adrenal crisis and long-term neurological complications. Early genetic testing and continued follow-up remain key to improved survival and quality of life.