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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0687
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 10 3713-3717
Copyright © 2006 by The Endocrine Society

CLINICAL CASE SEMINAR

Unusual Presentation of Familial Glucocorticoid Deficiency with a Novel MRAP Mutation

Dalit Modan-Moses1, Bruria Ben-Zeev1, Chen Hoffmann, Tzipora C. Falik-Zaccai, Yoram A. Bental, Orit Pinhas-Hamiel and Yair Anikster

Pediatric Endocrinology Unit (D.M.-M., O.P.-H.), Pediatric Neurology Unit (B.B.-Z.), and Metabolic Disease Unit (Y.A.), The Edmond and Lily Safra Children’s Hospital, and Department of Diagnostic Imaging (C.H.), Sheba Medical Center, Tel-Hashomer 52621, Israel; Division of Medical Genetics (T.C.F.-Z.), Hospital of Western Galilee-Naharia, Naharia 22386 Israel; Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel; Department of Neonatology (Y.A.B.), Laniado Medical Center, Netanya 42150, Israel; and the Sackler School of Medicine (D.M.-M., B.B.-Z., O.P.-H., Y.A.), Tel Aviv University, Tel Aviv 69978, Israel

Address all correspondence and requests for reprints to: Dalit Modan-Moses, M.D., Division of Pediatrics, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail: dmodan{at}sheba.health.gov.il.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Mutations in MRAP, an interacting partner of the ACTH receptor, have been shown recently to cause familial glucocorticoid deficiency (FGD) in kindreds with confirmed FGD and no ACTH receptor mutations.

Objective: We describe a Jewish-Ethiopian family with FGD caused by a novel MRAP mutation.

Patients: Our index patient presented at the age of 19 months with hypocortisolism, severe psychomotor retardation, myoclonic seizures, spastic quadriparesis, and microcephaly. Before the definite diagnosis was made, a female sibling was born in another hospital and succumbed during the neonatal period due to sepsis and adrenal crisis.

Methods: DNA was extracted from peripheral blood samples from the index case and his mother and from fibroblasts obtained from the female patient. The DAX-1, ACTH receptor (MC2R), and MRAP genes were analyzed.

Results: The index patient was diagnosed with FGD and was found to be homozygous for a novel MRAP mutation, a seven-base deletion in exon 3 of the MRAP gene. This deletion causes a frame shift, resulting in a stop codon after 23 amino acids (L31X). Postmortem analysis of fibroblasts obtained from the female patient revealed that she harbored the same mutation.

Conclusions: This is the first report of MRAP mutations after the recent identification of the gene. Whether the novel MRAP mutation described by us is associated with a particularly severe phenotype remains to be investigated.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
FAMILIAL GLUCOCORTICOID deficiency (FGD) is a rare autosomal recessive disorder characterized clinically by severe glucocorticoid deficiency associated with failure of adrenal responsiveness to ACTH but no mineralcorticoid deficiency. Patients suffer from recurrent hypoglycemia and convulsions that may result in coma and death, hyperpigmentation, recurrent infections, and failure to thrive (1, 2).

Homozygous or compound heterozygous inactivating mutations of the G protein-coupled ACTH receptor [melanocortin-2 receptor (MC2-R)] are found in 25–40% of FGD kindreds (3, 4, 5, 6, 7, 8, 9, 10), but the etiology of the disease in the remaining families has remained unknown (9, 11, 12, 13). Accordingly, Weber et al. (7) proposed classifying FGD into types 1 and 2, with and without MC2-R mutations, respectively.

A second locus at 8q12.1–21.2 was found to be associated with FGD in a single family (14).

Recently Metherell et al. (15) demonstrated that mutations in MRAP, encoding a new interacting partner of the ACTH receptor, caused FGD in 19 of 104 kindreds with confirmed FGD and no ACTH receptor mutations.

In the current paper, we describe a family with an unusual presentation of FGD due to a novel MRAP mutation.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Index case

The patient was referred to our center at the age of 19 months for evaluation because of severe psychomotor retardation, myoclonic seizures, spastic quadriparesis, and microcephaly.

The patient was a male who was born to nonconsanguineous Jewish-Ethiopian parents after an uneventful vaginal delivery at 40 wk of gestation, with a birth weight of 2850 g. According to the mother, he required assisted ventilation for several days but then stabilized and could be discharged home.

Past medical history was remarkable for two hospitalizations with pneumonia in another medical center, during which cortisol deficiency was diagnosed. Replacement treatment with glucocorticoids was recommended, but there was poor compliance to the treatment because of cultural barriers.

The patient was the fourth child; his three older siblings were healthy.

At the initial evaluation in our center, he showed severe microcephaly with a head circumference of 41 cm (–5.3 SD), severe spastic quadriparesis, profound mental retardation with no visual fixation or following, no response to auditory stimuli, and no other developmental milestones. During the examination he had very frequent myoclonic jerks and partial motor seizures. Hyperpigmentation could not be noticed because the patient was dark skinned. The external genitalia showed normal development with bilateral cryptorchidism. There were no signs of achalasia or alacrima.

Electroencephalography revealed diffuse slowing with intermittent multifocal spikes.

Magnetic resonance imaging (MRI) demonstrated brain atrophy of both gray and white matter accompanied by areas of encephalomalacia more prominent over the occipital region with a thin corpus callosum (Fig. 1Go). These findings were interpreted as compatible with hypoglycemia.


Figure 1
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  		FIG. 1. A, Spoiled-gradient recalled (SPGR) coronal image demonstrating severe atrophy with cystic changes in the white matter of both hemispheres. The cerebellum is intact. B, T2 axial image at the level of the basal ganglia demonstrating that the atrophy is more pronounced in the frontal lobes, with the same cystic appearance of the white matter.

 
Endocrinological analysis revealed an undetectable cortisol level (<0.1 µg/dl); extremely elevated ACTH (>1250 pg/ml); prepubertal LH, FSH, and testosterone (<0.1, 0.8, and <0.2, respectively); and normal levels of renin, free T4, and TSH. Serum electrolytes were within the normal range (Na = 137 mEq/liter, K = 4 mEq/liter).

A serum very long-chain fatty acid profile was normal. Plasma-free carnitine and acylcarnitines, pyruvate, lactate, ammonia, and amino acids (qualitative) were all normal (Table 1Go).


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  		TABLE 1. Laboratory results for the index patient

 
Patient’s sister

A sister was born in another center when our patient was 20 months old, before the diagnosis was made. The family did not inform us of the pregnancy, nor did they inform the other center of the index case’s condition. She was the product of an uneventful pregnancy, born at term, with a birth weight of 3750 g. Soon after birth, persistent hypoglycemia as well as hypotonia was observed. Endocrinological evaluation revealed an undetectable cortisol level (<0.1 µg/dl), with no response to ACTH injection. Serum very long-chain fatty acid profile was normal. At the age of 19 d, there was deterioration in her condition with severe hypotension and metabolic acidosis that did not respond to aggressive treatment with dopamine, Dobutrex, adrenalin, bicarbonate, and steroids. The baby died on her 21st day of life. Blood cultures (results obtained after death) were positive for Escherichia coli.

Methods

DNA was extracted from peripheral blood samples from the index case and his mother and from fibroblasts obtained from the female patient.

PCR amplification was performed using Ready-To-Go PCR beads (Amersham Pharmacia Biotech, Piscataway, NJ) with 10 pmol each primer in a total volume of 25 µl. The amplification conditions of the fragments were: initial denaturation at 96 C for 4 min, followed by 35 cycles at 94 C for 1 min, annealing at the appropriate temperature (Table 2Go) for 45 sec, and 72 C for 1 min, ending with a single 5-min extension step at 72 C.


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  		TABLE 2. Primers for PCR amplification of the MRAP, MC2R, and DAX-1 genes

 
Primers for the PCR experiments were designed based on the DAX-1, MRAP, and ACTH receptor (MC2R) genes.

Automated sequencing was performed on an ABI PRISM 3100 genetic analyzer, by using the BigDye Terminator cycle sequencing kit, according to the manufacturer’s protocol (Applied Biosystems, Foster City, CA).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Three genes were examined: DAX-1, MRAP, and the ACTH receptor gene (MC2R). The DAX-1 and ACTH receptor gene sequences were normal (data not shown). However, we identified a novel seven-base deletion in exon 3 of the MRAP gene. This mutation 17_23 deletion causes a frame shift, resulting in a stop codon L31X after 23 amino acids. The patient was homozygous for this mutation, and the mother was found to be a heterozygote (Fig. 2Go). Subsequently we received the DNA extracted from fibroblasts of the female patient. Analysis of exon 3 of the MRAP gene revealed that she was homozygous for the same 7-bp deletion.


Figure 2
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  		FIG. 2. Sequence of exon 3 of the MRAP gene of the subject and his mother. The subject was homozygous for a 7-bp deletion (17–23 acgcctc), whereas the mother was heterozygous for the same deletion.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In the current study, we describe a patient who presented with hypocortisolism and severe neurological disability, including severe psychomotor retardation, myoclonic seizures, spastic quadriparesis, and microcephaly. Based on the typical MRI findings and lack of evidence for any metabolic disorder, we concluded that the neurological abnormalities were solely due to recurrent and severe hypoglycemic episodes secondary to the hypocortisolism.

Neonatal and infantile hypoglycemia is one of the leading causes of brain injury (16). Neurological sequelae of hypoglycemia include microcephaly, mental retardation, cerebral palsy, visual disturbances associated with injury of the occipital lobes, and epilepsy of different types, including infantile spasms and partial seizures (17, 18, 19). Both the severity and length of hypoglycemia appear to affect the risk for permanent brain damage (16). However, when concomitant insults that increase cerebral demand for glucose, such as hypoxemia and ischemia, accompany hypoglycemia, the risk for encephalopathy appears to be higher (17, 18). Recurrent episodes of hypoglycemia increase the risk for long-term sequelae and are a more predictable factor for long-term effects than the severity of a single hypoglycemic episode (19). Typical MRI findings after neonatal and infantile hypoglycemia include diffuse cortical and subcortical white matter damage and brain parenchymal loss, especially of the parietal and occipital lobes, with generalized thinning of the cortex throughout the brain (20, 21).

Whether the profound neurological damage of our patient can attributed exclusively to hypoglycemia is debatable. However, the typical MRI findings, as well as the lack of evidence for any other metabolic disorder, support this assumption.

The differential diagnosis of adrenal insufficiency in infancy includes congenital disorders such as congenital adrenal hyperplasia, adrenal hypoplasia congenital, adrenoleukodystrophy (ALD); ACTH resistance syndromes (FGD, Allgrove syndrome, and Kearns-Sayre syndrome) (22); and acquired conditions such as adrenal hemorrhage, trauma, and infections (13). Initially ALD was suspected because this disease could explain both the neurological and endocrine disturbances. However, ALD was excluded by a normal very long-chain fatty acid profile as well as the MRI findings. 21-Hydroxylase deficiency, which is the most common cause of congenital adrenal hyperplasia, was unlikely in our patient because he had no evidence of mineralocorticoid deficiency. Congenital adrenal hypoplasia was also unlikely because he had well-virilized genitalia and no mutation of the DAX-1 gene.

Normal blood pressure, serum electrolytes, and serum aldosterone in the presence of a low serum cortisol and elevated ACTH level suggested isolated glucocorticoid deficiency. Because he had normal tear production and no evidence of achalasia, Allgrove syndrome was excluded. Thus, FGD became the most likely diagnosis. Further analysis demonstrated no mutation in the MC2R gene, but the patient was found to be homozygous for a novel seven-base deletion in exon 3 of the MRAP gene. Of interest, the novel mutation we identified resides in the same exon in which six of seven mutations have been described previously (15). The mutation we identified, Del 17–23, causes a frame shift, resulting in a stop codon L31X after 23 amino acids. The patient’s mother was found to be heterozygous to this deletion, whereas his deceased sister was homozygous for the same 7-bp deletion. Unfortunately, DNA from the father was not available to us. However, given that the mother was heterozygous and the two siblings were homozygous for the same mutation, uniparental isodisomy would be highly unlikely, and the father was most likely a carrier.

FGD, an autosomal recessive disorder, was first described in 1959 (1). The age of presentation is variable, with about half of the patients presenting in the first year of life. In the neonatal period, patients usually present with hypoglycemia and jaundice. Hypoglycemia and hyperpigmentation secondary to increased production of MSH are the main symptoms in older children. Other presenting features include feeding problems, regurgitation, failure to thrive, asthenia, and frequent and severe infections. Although the clinical signs of FGD resemble those of Addison’s disease, patients with FGD never develop mineralocorticoid deficiency (23).

The diagnosis of FGD is based on clinical findings, low serum cortisol in the presence of excessively elevated ACTH, proof of normal aldosterone production, and the exclusion of other causes of adrenal failure. The cloning of the ACTH receptor gene, MC2R (24), followed by the recent identification of MRAP mutations (15) made molecular diagnosis possible in many more patients.

MRAP is an essential cofactor for MC2R expression in certain cell types and seems to have a role in the processing, trafficking, or function of MC2R (15).

Although there is a significant phenotypic variability among FGD patients, data regarding genotype-phenotype correlation are inconsistent. Thus, some investigators reported that patients with MC2R mutations were clinically indistinguishable from patients without mutations (9, 11); whereas others reported that FGD-1 was associated with tall stature, increased growth rate, and a characteristic facial appearance, whereas FGD-2 patients tended to be of normal height. It has been suggested that these features may be mediated by ACTH actions through other melanocortin receptors (25, 26, 27).

Moreover, considerable variation in clinical phenotype exists, even for patients with identical mutations of the MC2R, and correlation between the estimated severity of the receptor defect in vitro and the degree of clinical severity is poor (28).

Our index patient presented with profound psychomotor retardation, myoclonic seizures, spastic quadriparesis, and microcephaly, whereas his sister succumbed in the neonatal period with septic shock and severe hypoglycemia. The particularly severe phenotype in this family may be attributed to the novel MRAP mutation described by us. Alternatively, the severe sequels in both patients may be the result of delayed diagnosis and treatment. This family illustrates the importance of using both clinical and new molecular data in a relentless effort for establishing a definite diagnosis in unique cases, allowing for identification of future cases both pre- and postnatally.


   Acknowledgments
 
The authors thank the excellent molecular work of H. Gore and N. Goldstein.


   Footnotes
 
First Published Online July 25, 2006

1 D.M.-M. and B.B.-Z. contributed equally to the study. Back

Abbreviations: ALD, Adrenoleukodystrophy; FGD, familial glucocorticoid deficiency; MC2-R, melanocortin-2 receptor; MRI, magnetic resonance imaging.

Received March 29, 2006.

Accepted July 17, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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