We present a 6-week-old male infant with persistent hyperbilirubinemia, hypertriglyceridemia, elevated creatine kinase levels, and transaminitis since the second week of life. When he developed hyperkalemia, clinical suspicion was raised for adrenal insufficiency despite hemodynamic stability. A full endocrine workup revealed nearly absent adrenocorticotropic hormone. Coupled with his persistent hypertriglyceridemia (peak of 811 mg/dL) and elevated creatine kinase levels (>20 000 U/L), his corticotropin level lead to a clinical diagnosis of complex glycerol kinase deficiency (GKD), also known as Xp21 deletion syndrome. This complex disorder encompasses the phenotype of Duchenne muscular dystrophy, GKD, and congenital adrenal hypoplasia due to the deletion of 3 contiguous genetic loci on the X chromosome. Our case exemplifies the presentation of this disorder and highlights the important lesson of distinguishing between adrenal hypoplasia congenita and congenital adrenal hyperplasia, as well as the sometimes subtle presentation of adrenal insufficiency. To our knowledge, it is also the first reported case of complex GKD deficiency with the additional finding of hepatic iron deposition, which may indicate a potential area for exploration regarding the pathogenesis of liver injury and cholestasis seen in cortisol-related endocrinopathies.
- AHC —
- adrenal hypoplasia congenita
- CK —
- creatine kinase
- DMD —
- Duchenne muscular dystrophy
- GKD —
- glycerol kinase deficiency
- NR0B1 —
- Nuclear Receptor Subfamily 0, Group B, Member 1
Adrenal hypoplasia congenita (AHC) is a rare cause of congenital adrenal insufficiency that often presents early in life, with salt wasting and hypoglycemia leading to growth failure and hemodynamic crises.1 It may present similarly to the more common congenital adrenal hyperplasia, but has important clinical distinctions, such as the potential for hyperpigmentation, cryptorchidism and other signs of hypogonadotropic hypogonadism, and associated disorders. AHC can be autosomal recessive or present as part of a contiguous X-linked recessive genetic syndrome together with glycerol kinase deficiency (GKD) and Duchenne muscular dystrophy (DMD), which is then often labeled complex GKD or Chromosome Xp21 deletion syndrome due to the position of all 3 loci on the short arm of the X chromosome.2 Isolated GKD can cause metabolic acidosis and hypoglycemia but is usually asymptomatic and detected incidentally through hyperlipidemia testing, as it causes a pseudohypertriglyceridemia.3 Complex GKD, however, carries a much more serious prognosis, as it can lead to life-threatening adrenal crises if unrecognized.
The case was a 3100-g 6-week-old male infant transferred to our NICU for further evaluation of persistent hyperbilirubinemia, hypertriglyceridemia, elevated creatine kinase (CK) levels, and transaminitis. He was born at 40 weeks’ gestation by spontaneous vaginal delivery to a 30-year-old gravida 1 para 0 mother who was Group B Streptococcus positive but otherwise had unremarkable prenatal serologies. Apgar scores were 9 and 9 at 1 and 5 minutes, respectively, and birth weight was 2946 g. Mother received adequate intrapartum antibiotic prophylaxis but was diagnosed with chorioamnionitis; thus, the patient received 48 hours of antibiotics at birth. He was also noted to have mild jaundice in the first few days of life attributed to ABO incompatibility, although his hemoglobin levels showed no evidence of hemolysis.
On day of life 5, he became febrile, lethargic, and more jaundiced. He developed severe refractory hypotension and respiratory failure. Laboratory testing revealed a significant coagulopathy (international normalized ratio 3.9), hyponatremia, and hyperkalemia in the setting of significant oliguria. He was also noted to have signs of end-organ ischemia with an elevation in his troponins, creatinine, transaminases, and CK levels. He was managed with broad-spectrum antibiotics for presumed sepsis, and with multiple vasopressors and hydrocortisone for his refractory hypotensive shock. He received intramuscular vitamin K and fresh-frozen plasma transfusions over several days until normalization of his international normalized ratio.
Extensive infectious workup, including bacterial, viral, and fungal studies, remained negative. He slowly improved and was weaned from the ventilator and all blood pressure support, including steroids. All laboratory values normalized with the exception of his direct bilirubin, CK levels, and transaminases, with his aspartate aminotransferase and alanine aminotransferase showing a persistent fivefold elevation despite discontinuation of parenteral nutrition. He was further noted to have elevated triglyceride levels up to maximum of 811 mg/dL despite being fed several different types of formula.
Given the continued elevation in his bilirubin and transaminases, he received an extensive gastrointestinal workup, including normal abdominal imaging (ultrasound and upper gastrointestinal series), normal pancreatic enzyme and ammonia levels, and negative hepatitis serologies. A hepatobiliary iminodiacetic acid scan conducted at 1 month of life revealed no excretion of tracer from the liver; thus, a liver biopsy was done, which revealed focal intracellular cholestasis with giant cell transformation of some hepatocytes and moderately increased iron stores, but no steatosis, fibrosis, necrosis, inflammation, or features of biliary atresia. The hepatic siderosis raised concerns for neonatal hemochromatosis, a phenotype of severe liver disease with extrahepatic iron deposition that can result from various causes.4 Our patient underwent a buccal biopsy to look for iron staining and a brain MRI to look for iron deposition, but these were both normal. He was evaluated for inborn errors of metabolism that can cause liver disease, such as galactosemia, tyrosinemia, or α-1 antitrypsin deficiency, and was found to have borderline elevated levels of acylcarnitines known to be falsely elevated by parenteral nutrition. Otherwise this workup was negative.
Given the persistent laboratory abnormalities, transfer to our NICU was requested. On admission, he was clinically stable, but his weight was below the third percentile, down from the 15th percentile at birth. Examination revealed cryptorchidism, scleral icterus, and mild hypotonia, but notably no hepatomegaly. He also had extremely dark skin, which the parents reported was not present at birth but had developed quickly after birth. The remainder of the examination was normal. Laboratories in the first week of admission revealed normal electrolytes but continued hypertriglyceridemia, cholestasis, transaminitis, and CK elevations (Table 1). We investigated for inborn errors of bile acid metabolism by sending total and fractionated bile acid levels, as elevations of unusual bile acids have been associated with severe cholestasis and subsequent liver damage.5,6 Although our patient’s total bile acid levels were elevated (>128 μmol/L), his profile indicated nonspecific cholestasis given the predominance of primary bile acids.
Over the next 2 weeks, he remained hospitalized working on oral feeds. Routine laboratories at 7 weeks of age revealed hyponatremia (130 mmol/L) and hyperkalemia (8.1 mmol/L) with normal renal function (creatinine 0.18 mg/dL) and good urine output on full enteral feeds and no medications. Although he remained hemodynamically stable, his ongoing lack of a unifying diagnosis and these laboratory findings led to an investigation of his adrenal function. Both his cortisol (2.0 μg/dL) and aldosterone (<3.0 ng/dL) levels were abnormally low. Concurrent plasma adrenocorticotropic hormone and plasma renin activity levels were noted to be extremely elevated at 3192 pg/mL (normal 5–46 pg/mL) and 66 ng/mL per hour (normal for age <37 mg/mL per hour), respectively. Combining this evidence of adrenal hypofunction with his elevated CK levels, complex GKD was suspected. The laboratory was asked to correct his triglyceride levels for serum glycerols, which revealed a true triglyceride level within the normal range. Furthermore, glycerol kinase levels were confirmed to be elevated at 4384 μmol/L (normal 13–66 μmol/L).
Ultimately, a comparative genomic hybridization microarray study was done, which confirmed an Xp21 deletion (Table 2). His mother was also found to be a carrier of this deletion by fluorescence in situ hybridization study.
Our patient was started on replacement fludrocortisone and hydrocortisone; within 4 days, his plasma renin activity levels normalized. Over the course of the next few weeks, his hyperpigmentation, feeding skills, and weight gain also improved and he was discharged from the hospital.
GKD can exist alone as an isolated deficiency and may cause a Reye-like syndrome of vomiting, metabolic acidosis, and ketotic hypoglycemia due to hyperglycerolemia and glyceroluria.2 However, it is often asymptomatic and discovered incidentally later in life through hyperlipidemia testing, given many laboratories’ standard methodology of reporting serum triglycerides indirectly by measuring serum glycerol levels.3,7 When patients are also missing either of both the dystrophin gene and/or the Nuclear Receptor Subfamily 0, Group B, Member 1 (NR0B1) gene, the condition is known as complex GKD or Chromosome Xp21 deletion syndrome due to the contiguous position of all 3 loci on the short arm of the X chromosome.2 Each gene deletion contributes to the phenotype, with the deletion of the dystrophin gene causing weakness and muscle breakdown consistent with DMD, the deletion of the NR0B1 gene causing AHC due to a deficiency of the DAX-1 protein and finally, the deletion of the glycerol kinase gene causing elevated glycerol levels.8 When all 3 genes are deleted, the presentation of this recessive X-linked condition is more severe and occurs in the infantile period. Due to the involvement of NR0B1 in gonadal development, cryptorchidism may be present, as in our patient, and there is potential for later hypogonadotropic hypogonadism during puberty.8
Most patients with complex GKD involving the AHC loci will present with an acute adrenal crisis in the first few weeks to months of life. Our patient’s presumed septic crisis in the first week of life was likely his first manifestation of his AHC. When an infant presents with symptoms of adrenal insufficiency, clinicians must rightly consider congenital adrenal hyperplasia, as it has a much higher incidence of 1:5000 to 1:15 000 compared with 1:140 000 to 1:1 200 000 for AHC.8,9 Importantly, AHC usually presents with normal 17-hydroxyprogesterone levels, excluding the most common cause of congenital adrenal hyperplasia.10–12 In addition, given AHC’s involvement of the entire adrenal gland, it has the potential for an Addisonian-like presentation of hyperpigmentation, which can help differentiate it from other forms of adrenal insufficiency. Our patient was born with light brown skin (Fig 1), which darkened significantly in the first week of life (Fig 2).
We believe our patient’s persistent direct hyperbilirubinemia with biopsy-confirmed cholestasis was also likely related to his AHC. The relationship between cortisol deficiency and cholestasis has been well-described.13 Although the mechanism is not well understood, it may be related to cortisol’s effect on bile formation. In 1 case series of 4 neonates with severe cortisol deficiency, cholestasis resolved with hydrocortisone replacement.13 We witnessed this same pattern in our patient, whose direct bilirubin peaked at 8.9 mg/dL but improved down to 3.6 mg/dL after replacement steroid therapy.
Our patient, however, uniquely exhibited iron deposition on his liver biopsy. To our knowledge, hepatic siderosis has not been previously documented in any of the reported cases of isolated AHC, GKD, DMD, or complex GKD. It is possible that his siderosis was related to other etiologies. For instance, hepatic siderosis has been documented in cases of neonatal acute liver failure.14 Our patient’s history of coagulopathy, transaminitis, and direct hyperbilirubinemia during his early hypotensive shock episode indicate that he likely suffered at least acute hepatic injury; however, his coagulopathy quickly improved and he never developed episodes of bleeding, ascites, or hepatomegaly. Additionally, the liver biopsy did not have any of the hepatocyte loss, inflammation, or necrosis typically associated with acute liver failure, or any cirrhosis or fibrosis indicative of chronic liver injury.
There have, however, been several case reports of patients with adrenal insufficiency who were found to have increased hepatic iron deposition.15,16 In addition, there is at least 1 reported case of improvement in liver failure after corticosteroid replacement for adrenal insufficiency, possibly indicating a relationship between these 2 disease processes.17 Given this literature, it is possible that our patient’s siderosis was related to his adrenal hypofunction and not simply a manifestation of our patient’s initial acute hepatic injury. Future efforts to understand this contiguous deletion syndrome may therefore benefit from the exploration of the potential link among adrenal insufficiency, hepatic iron deposition, and cholestatic liver injury.
It is important for clinicians to consider AHC and its associated genetic syndromes when evaluating infants with suspected adrenal insufficiency. Further studies focused on the relationship between cholestasis and cortisol deficiency are warranted, as they may provide insight into the pathophysiology of disorders such as complex GKD.
The authors acknowledge the parents of this infant who gave informed consent to describe this patient for a case report and provided photographs.
- Accepted December 12, 2016.
- Address correspondence to Diana Montoya-Williams, MD, Department of Pediatrics, Division of Neonatology, University of Florida, PO Box 100296, Gainesville, FL 32610. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
- Leger J
- Chan D,
- Ng K,
- Ip PLS
- Copyright © 2017 by the American Academy of Pediatrics