The Severe neonatal presentation of Xp21 contiguous gene deletion: adrenal crisis and neuromuscular involvement

Background. Xp21 contiguous gene deletion syndrome is a rare X-linked disorder involving deletions of DMD, GK, and NR0B1 (DAX1), leading to a combination of Duchenne muscular dystrophy, glycerol kinase deficiency, and congenital adrenal hypoplasia. Diagnosis can be delayed due to overlapping symptoms, especially in critically ill infants.

Case Reports. We describe two male infants presenting in early life with adrenal insufficiency, electrolyte imbalance, hyperpigmentation, and hypotonia. Biochemical findings included elevated ACTH, low cortisol, high CK, and pseudo-hypertriglyceridemia. In the first case, delayed diagnosis led to sudden death at 7 months. In the second case, early clinical suspicion enabled timely genetic testing and family screening. MLPA revealed DMD gene deletion in both cases. In the second case, molecular karyotyping confirmed deletion at Xp21.3-p21.1; the mother and sister were also carriers.

Conclusion. Clinicians should consider Xp21 syndromes in male infants with adrenal insufficiency and neuromuscular or metabolic signs. Early recognition and genetic testing are crucial for accurate diagnosis, effective management, and informed family counseling.

Introduction

Genetic disorders involving the Xp21 chromosomal region represent a clinically heterogeneous group of conditions encompassing neuromuscular, adrenal, and metabolic pathologies. Notably, pathogenic variants and deletions affecting the DMD gene and adjacent loci can result in Duchenne muscular dystrophy (DMD), glycerol kinase deficiency (GKD), and X-linked adrenal hypoplasia congenita (AHC), often presenting with overlapping or atypical clinical phenotypes ^1-3. Recent advances in genetic diagnostics have significantly improved the detection and characterization of pathogenic variants within the Xp21 region. However, the phenotypic variability of these disorders remains a challenge, underscoring the importance of comprehensive clinical and genetic evaluation in affected infants ^4-6. Some infants may present with life-threatening manifestations of adrenal crisis, requiring immediate life-saving intervention, which may temporarily delay a thorough etiological evaluation and targeted genetic diagnosis. In this case series, we present two male infants with genetically confirmed Xp21-associated disorders. We describe their clinical features and diagnostic and management pathways to underscore the critical role of integrative clinical-genetic evaluation in achieving timely and accurate diagnosis. One case, unfortunately, resulted in early death due to diagnostic delay, highlighting the need for heightened clinical suspicion and rapid molecular testing. By sharing these cases, we aim to contribute to the early recognition and development of tailored therapeutic strategies for patients with these complex and often severe conditions ^7-9.

Case 1

An 8-day-old male newborn was admitted to the hospital due to persistent vomiting, poor feeding, weight loss (375 g from a birth weight of 2610 g), dehydration, and skin hyperpigmentation. Perinatal history was unremarkable, apart from being a twin pregnancy where the other twin brother was born healthy. The pregnancy was otherwise uneventful. The infant was born at 37 weeks gestation via spontaneous vaginal delivery, with a birth weight of 2610 g (10th percentile), a length of 47 cm (3rd percentile), and Apgar scores of 8.

On admission, the infant appeared lethargic, dehydrated, and hypotonic. Vital signs showed a pulse rate of 131 beats per minute and blood pressure of 70/38 mmHg. Clinical examination revealed hyperpigmentation of the perioral, buccal, and palmar regions. Genital examination showed bilateral cryptorchidism. No dysmorphic features were noted. Initial laboratory results showed hyponatremia (sodium 128 mmol/L), hyperkalemia (potassium 6.1 mmol/L), and hypoglycemia (glucose 2.2 mmol/L). Endocrinological evaluation revealed low serum cortisol (13 ng/mL; normal range: 150-500 ng/mL), markedly elevated ACTH (6870 pg/mL; normal: 7.2-66.3 pg/mL), low aldosterone (1.0 ng/mL), high plasma renin concentration (500 mIU/mL), and normal levels of 17-hydroxyprogesterone. An ultrasound of the adrenals revealed small adrenal glands for age. These findings were consistent with primary adrenal insufficiency ^7,8. Treatment was initiated with intravenous fluids and electrolytes, stress-dose hydrocortisone (100 mg/m²/day), and empiric antibiotics. Upon stabilization, oral hydrocortisone and fludrocortisone therapy were introduced, along with 3 g per da sodium chloride supplementation in the feeding formula. Over the next three weeks, he showed marked clinical improvement. However, pediatric endocrinology follow-ups were not conducted regularly due to the COVID-19 pandemic. At six months of age, the infant was readmitted with fever and significantly elevated transaminases (AST 2316 U/L, ALT 547 U/L). Laboratory findings included elevated creatine kinase (9516 U/L), normal serum electrolytes, and markedly increased triglycerides (7.1 mmol/L) with a non-turbid appearance, raising suspicion for pseudo-hypertriglyceridemia due to elevated free serum glycerol ^1,9. The patient tested negative for SARS-CoV-2 on several PCR tests.

On physical examination, the infant demonstrated hypotonia of the lower limbs with preserved tendon reflexes, the child was unable to roll over or support his head. Cardiac evaluation was normal. The constellation of pseudo-hypertriglyceridemia, elevated CK levels, and signs of adrenal and neuromuscular involvement suggested deletion in XP21 region [3]. MLPA revealed a hemizygous deletion of the DMD gene, confirming the diagnosis of Duchenne muscular dystrophy. Additional investigations, including molecular karyotyping, were planned ^2,3. Unfortunately, at seven months of age, the patient suffered sudden infant death at home. An autopsy was not performed.

Case 2

A 42-day-old male infant was admitted due to vomiting, poor feeding, weight loss (400 g), dehydration, and skin hyperpigmentation.

Perinatal history was unremarkable. The patient was the third child, first son. He was born at 39 weeks via spontaneous vaginal delivery, weighing 3590 g (60th percentile), Apgar 9.

The infant presented with severe dehydration, lethargy, reduced subcutaneous tissue, and hoarse cry. Labs showed severe hyponatremia (105 mmol/L), hyperkalemia (6.5 mmol/L), and normoglycemia. Significantly elevated transaminases (AST 225 U/L, ALT 94 U/L), CK (17750 U/L), LDH (1252 U/L), and triglycerides (11.8 mmol/L) were recorded. Endocrine evaluation revealed low cortisol (22 ng/mL), elevated ACTH (354 pg/mL), low aldosterone (1.3 ng/mL), high plasma renin (365 mIU/mL), and normal 17-hydroxyprogesterone ^4,7.

Ultrasound of the adrenals was normal. Cardiac evaluation was unremarkable. Treatment was initiated with fluids and hydrocortisone. After stabilization, oral hydrocortisone and fludrocortisone were continued along with sodium chloride supplementation. Clinical improvement followed. Genetic testing via MLPA revealed a hemizygous deletion of the DMD gene, confirming Duchenne muscular dystrophy. Molecular karyotyping revealed an 8.2 Mb deletion (arr (hg19) Xp21.3-p21.1 (25119054-337723252) which includes 19 protein-coding genes. The mother and one sister were also found to carry the same deletion, highlighting the importance of cascade testing ^1,3,9. At evaluation, neither the mother nor the sister presented muscular or heart problems. The mother had slightly raised serum CK levels, but her heart tests, including echocardiography and ECG, were normal. The sister had normal CK and normal clinical and cardiac exams. Both continue regular follow-up.

By 7 months of age, during ongoing follow-up, the patient exhibited generalized hypotonia and calf pseudohypertrophy. Alongside motor delay, mild slowing of cognitive development was noted. The infant demonstrated visual tracking but exhibited a diminished response to sounds, poor toy-handling skills, and reduced social interaction, with rare vocalizations and minimal social smiling. These findings warrant continued monitoring and early intervention, such as physiotherapy and developmental support.

Informed consent was obtained for the publication of this data.

Discussion

These cases illustrate diagnostic challenges in infants presenting with adrenal insufficiency and neuromuscular findings. In Case 1, diagnosis was delayed due to the COVID-19 pandemic and lack of clinical suspicion. Although endocrine findings suggested AHC, further neuromuscular assessment and genetic testing were not conducted early ^5,7. As a result, a syndromic diagnosis was missed, and genetic counseling was not initiated ^8,9.

Case 2 illustrates how prior clinical experience enabled timely diagnosis and family screening. Recognition of pseudo-hypertriglyceridemia, hyper-CKemia, and adrenal dysfunction led to suspicion of an Xp21 contiguous gene deletion syndrome ^1-3. Previous studies highlighted the diagnostic value of assessing glycerol kinase activity in tissue samples ¹⁰, however, this approach is invasive and is no longer routinely performed in current clinical practice. Instead, molecular genetic testing, combined with characteristic biochemical markers such as elevated free glycerol level and pseudohypertriglyceridemia, represents the current standard for diagnosis. In our center, free glycerol evaluation in serum and urin is not available as a routine procedure.

Early MLPA testing confirmed DMD deletion, allowing rapid counseling and testing of family members ^9,11.

Importantly, both infants presented with severe, life-threatening clinical manifestations, including adrenal crisis and metabolic instability. In such settings, urgent medical stabilization is the immediate priority, which may delay detailed diagnostic evaluation. This underscores the need for heightened clinical awareness and early suspicion of syndromic causes when critical symptoms coexist ². These findings align with previous reports emphasizing the need for early recognition of rare genetic causes of adrenal insufficiency, including DMD-GKD-AHC syndromes ^1,2,6.

Conclusion

Clinicians should consider syndromic diagnoses such as Xp21 contiguous gene deletion syndrome in male infants with adrenal insufficiency plus neuromuscular symptoms or unexplained metabolic findings like pseudo-hypertriglyceridemia ^1-3. Particular attention should be paid to critically ill infants, in whom life-threatening manifestations may obscure underlying syndromic etiologies. Prompt recognition and genetic testing can guide early management, improve outcomes, and allow timely family counseling.

Conflict of interest statement

The authors declare that there is no conflict of interest to disclose.

Funding

The authors declare that the study received no funding.

Authors contributions

S.S.: study main author. T.S.: Study conception and design. M.I.: data collection. M.J.: draft manuscript preparation. M.A.: analysis and interpretation of results.

History

Received: June 15, 2025

Accepted: July 14, 2025