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Familial Occurrence of the IMAGe Association: Additional Clinical Variants and a Proposed Mode of Inheritance

Centro de Investigaciones Endocrinológicas (I.B., G.d.R., C.B., S.C.), Hospital de Niños "Ricardo Gutiérrez," 1425 Buenos Aires, Argentina; Servicio de Genética (P.L.), Hospital La Paz, 28046 Madrid, Spain; Human Genetics (M.F.), Institut National de la Santé et de la Recherche Médicale U361, E0021, Hôpital Cochin, 75014 Paris, France; and Laboratorio de Biología Molecular (S.C.), Departamento de Ciencias Biológicas, Universidad CAECE, 1918 Buenos Aires, Argentina

Address all correspondence and requests for reprints to: Ignacio Bergadá, M.D., Hospital de Niños "R. Gutiérrez," División de Endocrinología, Gallo 1330, Buenos Aires (1425), Argentina. E-mail: ibergada{at}cedie.org.ar.

	Abstract

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The IMAGe (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies) association (online inheritance in man 300290) is a recently reported disorder comprising intrauterine growth retardation (IUGR), metaphyseal dysplasia, adrenal hypoplasia, and genital anomalies. Four children (three males, one female) from a large pedigree (five generations) were studied. Additional members (n = 10), who died during the neonatal period, were born with IUGR and/or hyperpigmentation and are presumed to have been affected, too. All patients in this series were diagnosed during the newborn period. Minimal clinical features and laboratory findings differ with previously reported patients, suggesting variants in their clinical expression. Adrenal insufficiency was variable within patients. All had severe IUGR and marked postnatal growth failure. Sequence analysis of DNA using an automated cycle from two patients revealed no mutation in the dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1. Analysis of the pedigree showed that the disease is inherited via the maternal line, even in the dead children with suspicion of the disease. Hence, the pattern of inheritance in this family of this unusual disorder might be explained in terms of the genomic imprinting hypothesis with expression through maternal transmission involving an autosomal gene. This transmission may have considerable implications for genetic counseling. Furthermore, pediatric endocrinologists must be aware of the possible occurrence of this life-threatening condition in the offspring of nonaffected women when related to a family member with the association of IUGR, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies.

	Introduction

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ADRENAL INSUFFICIENCY DURING the newborn period is a critical, life-threatening disorder. Early detection and rapid steroid replacement are critical for survival. Within its etiologies, X-linked adrenal hypoplasia congenita (AHC) represents a disease that affects the glucocorticoid and mineralocorticoid synthesis and frequently diagnosed early in life. Other patients display symptoms during childhood, referred as to late onset adrenal insufficiency (1, 2). Clinical spectrum of the disease is variable and frequently associated to hypogonadotropic hypogonadism (3, 4). The association with muscular dystrophy of the Duchenne type with deficiency of glycerol kinase led to the finding that this association is due to a contiguous gene deletion on the locus of the short arm of X chromosome. It has been shown that mutations in the dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1) gene, located in the Xp21 region of chromosome X, is responsible for both X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism in most of the cases; however, the clinical spectrum of patients with the DAX1 mutations is variable (5, 6, 7, 8).

Recently Vilain et al. (9) described three unrelated cases with AHC associated with other dysmorphic features and without anomalies of the DAX1 gene. They named this association IMAGe, characterized by intrauterine growth retardation (IUGR), metaphyseal dysplasia, adrenal insufficiency, and genital anomalies. Lienhardt et al. (10) and Ferey et al. (11) described additional clinical features of the disorder and suggested an autosomal recessive pattern of inheritance.

In the present report, we describe a large pedigree with four affected individuals (three males and one female). They had a variable pattern of adrenal insufficiency, intrauterine and postnatal growth retardation, genital anomalies, and skeletal changes characteristics of the IMAGe association (Table 1). An analysis of the pedigree suggests that in this family the mode of inheritance differs from what was previously reported.

	Patients and Methods

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View larger version (21K): [in this window] [in a new window]   FIG. 1. Pedigree of the family.

Patient reports

Patient 1(IV-38). Born at 36 wk of gestation to nonconsanguineous healthy parents, he had mild respiratory distress and apparent sepsis treated with antibiotics. Subsequently, from the 11th to 33rd day of life before referral to our hospital, he had several episodes of dehydration with hyponatremia and hyperkalemia. Serum aldosterone was inadequately low for the level of hyponatremia and an elevated serum ACTH with a normal basal cortisol (Table 2). Adrenal insufficiency was suspected, and he was treated with hydrocortisone, fludrocortisone, and sodium chloride. At the age of 2.5 months on referral, his weight was 2450 g (less than the third centile), length was 46 cm (–5.8 SD), and head circumference 35 cm (third to 10th centile). Physical examination showed hyperpigmentation, frontal bossing, small low-set ears, mild flattened nasal bridge, normal penis, and unilateral cryptorchidism with testicular volume less than 1 ml each. The blood karyotype was 46, XY. Sequencing DAX1 gene identified no mutation.

At 13 yr 5 months, his height was 122 cm [–3.78 (SDS)], weight 22.5 kg, and bone age 10.5 years. Physical exam showed pubic hair Tanner stage 3, genital Tanner stage 2–3, and mild increment in testicular volume (2–3 ml each) with a slightly short penis. Laboratory showed basal LH 1.1 mIU/ml, FSH 4.4 mIU/ml, testosterone 43 ng/dl (1.48 nmol/liter), and inhibin B 171 pg/ml [reference Tanner stage II, 234 ± 25 pg/ml (SEM)]. Urinary calcium to creatinine ratio was 0.03 (normal < 0.2). A renal ultrasound was normal without evidence of nephrocalcinosis. Intellectual development was normal.

Patient 2 (V-15). This boy was born at 38 wk of gestation to nonconsanguineous healthy parents. His oldest brother died after birth and a younger brother is healthy. During the first week, he developed generalized hyperpigmentation, weakness, and vomiting and was admitted to a regional hospital due to severe dehydration, hyponatremia, and hyperkalemia (Table 2). Because his phenotype and laboratory results were similar to his uncle (patient 1), he was treated with hydrocortisone and fludrocortisone, promptly recovered, and lately referred to our hospital. At 1 yr 8 months of age after 1 d of hydrocortisone withdrawal, an iv ACTH test showed no increment in serum cortisol (Table 2). At physical examination at the age of 2 yr 9 months, height was 82.5 cm (–2.7 SDS), weight 10.2 kg (less than the third centile), and head circumference 46.5 cm (10th centile). Physical examination showed frontal bossing, low-set ears, normal penis, and unilateral cryptorchidism with a testicular volume of less than 1 ml each. High-resolution karyotype was 46, XY. Sequencing DAX1 gene identified no mutation.

At the age of 5 yr 11 months, bone age was 2.5 yr. At age 7 yr, height was 107.1 cm (–2.84 SDS). No scoliosis was noticed and a hand x-ray showed only mild flaring of distal radio and ulnae. Urinary calcium to creatinine ratio was 0.05. A renal ultrasound was normal without evidence of nephrocalcinosis. Intellectual development was normal.

Patient 3 (V-3). This girl was born at 39 wk of gestation to nonconsanguineous healthy parents. Her oldest sister (V-2) was also born with IUGR and died during the newborn period without diagnosis. At 25 d of age, she was referred to another hospital due to failure to thrive associated with dysmorphic features. Hyponatremia and hyperkalemia were also noticed with low serum aldosterone (Table 2). She was diagnosed as having primary hypoaldosteronism and was treated with fludrocortisone and sodium chloride. At 3 months of age, her blood pressure was 119/88 mm Hg, with serum sodium and potassium of 139 and 5.5 mEq/liter, respectively. She was assumed to have a transient hypoaldosteronism and fludrocortisone was withdrawn. Her last visit was at 4 months of age, and her parents reported that she remained healthy. High-resolution karyotype was 46, XX.

At 8 months of age, she was admitted to the medical emergency department of our hospital with a septic shock due to a urinary tract infection. Upon admission, cardiopulmonary resuscitation was performed. She was treated with fluids, antibiotics, and iv hydrocortisone. Facial phenotype was similar to patients 1 and 2: short stature with frontal bossing and low-set ears. She developed a severe respiratory distress syndrome and eventually died 5 d later.

Patient 4 (V-1). This boy was born at 37 wk of gestation to nonconsanguineous healthy parents. Birth length was 40.5 cm. After the first 2 wk of life, he lost weight. Laboratory results showed hyponatremia and hyperkalemia. At 39 d of life, he was admitted to our hospital, mildly dehydrated with a weight of 1545 g, height 41 cm, and head circumference of 33.5 cm. Physical examination showed frontal bossing, wide nasal bridge, small low-set ears, short neck, right cryptorchidism, and clinodactyly of both fifth toes and fingers. Laboratory results showed a serum sodium of 119 mEq/liter and serum potassium of 6.6 mEq/liter, with moderately low serum aldosterone with high renin and normal cortisol with elevated ACTH (Table 2). Urinary calcium to creatinine ratio 0.1 (normal < 0.8). He was treated with hydrocortisone, fludrocortisone and sodium chloride. Under replacement therapy his serum electrolytes were normal, serum ACTH 205 pg/ml (45 pmol/liter), and urinary calcium to creatinine ratio 0.94. At 7 months of life, urinary calcium to creatinine ratio was 1.9. On his last visit at 8.5 months, his height was 56.5 cm (–6.1 SDS) and weight of 4830 g.

	Discussion

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In the present study, we present four patients belonging to a large pedigree with clinical, radiological, and laboratory characteristics of the recently recognized syndrome referred as the IMAGe association (9, 10). In addition, our studies suggest that this pedigree has a complex pattern of inheritance.

IUGR is a striking feature in all four patients as it was in all eight previously reported (9, 10, 11, 12). Furthermore, some other relatives of our patients who may have been affected and died during the newborn period had IUGR as well (III-19–24, V-2, V-14, V-17, V-19) (Fig. 1). GH secretion, in one of our patients (IV-38), was studied and it was normal. Only two patients previously reported having attained final heights that were –2.6 and –3.5 SDS, respectively (10). One patient with the IMAGe association with subnormal GH secretion after a glucagon stimulation test has shown a poor response to GH therapy (12). In another report of a boy with the IMAGe association and normal GH secretion, GH treatment was introduced with a height gain in 2 yr similar to that observed in patients with IUGR receiving GH (13). We believe that although more information regarding height prognosis on these patients is necessary, starting GH treatment (1 IU/kg·wk) at early ages would be a beneficial approach.

Bone dysplasia was noticed in patient 1 (IV-38) but appeared to be mild; however, he had severe scoliosis. Patient 2 (V-15) also showed mild metaphyseal dysplasia on his hand x-ray. Osteoporosis, short ribs, wide dysplastic metaphyses and narrow growth plate were observed in previous patients (9, 10, 11, 12) (Table 1). Furthermore, previous reports have shown that bone dysplasia may be observed after 3–4 yr of age and that skeletal anomalies do not have a specific pattern of well-defined chondrodysplasia (9).

Upon the description of hypercalciuria in some patients with the IMAGe association, we explored the calcium to creatinine ratio in the two eldest patients (IV-38, V-15), and in both the calcium to creatinine ratio as well as their renal ultrasound was normal (9). Both patients were on a normal diet without sodium supplementation. In patient 4 (V-1), calcium to creatinine ratio was normal before treatment but was further elevated while receiving supplements of sodium chloride. Because the excess of sodium ingestion is a cause of hypercalciuria, we cannot exclude that in the previously reported patients with hypercalciuria, it might have been secondary to an excess of sodium supplementation or may well be clinical variants of this association.

The adrenal hypoplasia appears to be have different degrees of deficiency within our patients. All of them, soon after birth, showed failure to thrive and recurrent episodes of dehydration concomitant with the presence of hyponatremia and hyperkalemia. In one of our patients (V-1), plasma aldosterone was normal, although it was inappropriately low for the degree of hyponatremia and plasma rennin levels. In two patients during the neonatal period, serum basal cortisol were normal or moderately elevated with high serum ACTH levels. Furthermore, patient 1 (IV-38) at 2 yr of age after hydrocortisone withdrawal remained clinically well compensated for 3 months; however, he had a normal basal cortisol with no further increment after the administration of exogenous ACTH. The apparently mild adrenal hypoplasia in some patients with the IMAGe association was shown with patient 3 (V-3) that was off medication at 3 months of age. In two patients previously reported, the diagnosis of adrenal insufficiency was made during childhood, one in a girl with recurrent episodes of vomiting since birth and very high levels of ACTH and another in a boy with hyperpigmentation and mild symptoms of fatigue (10, 12). Unfortunately, no information regarding their mineralocorticoid pathway was mentioned. All these data show that the adrenal hypoplasia exists in different degrees, but we believe all affected individuals deserve treatment because those moderately deficient may be at risk of developing an acute adrenal crisis under stress, especially during the neonatal period and infancy. In addition, several members of our pedigree (III-19–24, V-2, V-14, V-17, V-19) born small for gestational age (SGA) with hyperpigmentation died during the newborn period without diagnosis, although none were confirmed to have the IMAGe association; it is likely their deaths were secondary to adrenal insufficiency.

Genital anomalies in the IMAGe association have been described only in males. These may include bilateral cryptorchidism, micropenis, hypospadias, and bifid scrotum (9, 10, 12). In our patients the genital anomalies appeared to be milder than those previously described. Two patients had unilateral cryptorchidism and one of them had small testes. Similarly to one of the patients reported by Lienhardt et al. (10), our patient IV-38 developed puberty at a normal age, ruling out hypogonadism, as seen in many patients with X-linked AHC. At Tanner stage 3, however, this patient’s testicular volume was smaller than expected for his Tanner stage of genital development.

Lienhardt et al. (10) suggested an autosomal recessive pattern of inheritance after evaluating two pairs of female and male siblings. The pedigree of our family is complex and at the same time interesting because it may shed light on the possible mechanism of inheritance of the IMAGe association in some familial cases. It is important to emphasize that in addition to the four patients presented in this report, four additional relatives died with similar phenotype (V-2, V-14, V-17, and V-19). They were born SGA, and in some of them hyperpigmentation also was noticed. Furthermore, in III-19–24 (two females and four males), all had died during the neonatal period and were born SGA and with hyperpigmentation.

Two of our four patients had normal molecular studies for the Xp21 DAX1 gene. This fact agrees with the pedigree in which the male to male transmission was against a classical X-linked pattern of inheritance as has been seen in patients with AHC and DAX1 mutations. Other known genetic disorders associated to adrenal insufficiency deserve some considerations. Among those, the triple-A syndrome (Allgrove syndrome; autosomal recessive), the X-linked adrenoleukodystrophy (ABCD1 gene), and alterations of the CTLA-4 gene (observed in some types of autoimmune endocrinopathies) can be ruled out after the pedigree analysis and a careful review of associated clinical findings.

Moreover, all the patients and the affected relatives were born from clinically unaffected women whose fathers were related. Analysis of the pedigree shows that the disease is inherited exclusively via the maternal line, whereas along the paternal line never occurred, so far a finding inconsistent with the classical Mendelian genetics transmission. For this reason, the pattern of inheritance in this family might be explained in terms of the genomic imprinting hypothesis with expression through maternal transmission involving an autosomal dominant gene(s) (14). If we include the relatives of our patients with IUGR who may have been affected and died during the newborn period (III-19–24, V-2, V-14, V-17, V-19), the proposed imprinting hypothesis still remains the most plausible pattern of inheritance. The expression of the phenotype in this family appears to be expressed more severely through successive generations. Hence, we can suggest that an expansion of triplets of this autosomal gene and that an anticipation phenomena in the female meiosis would be a possible mode of inheritance of transmission in this family. The molecular mechanism in relation to the finding of unstable expanding trinucleotide repeats became respectable in patients with fragile X syndrome, myotonic dystrophy, and Huntington disease (15, 16, 17, 18).

We do not consider a mitochondrial disease in our family because the relatives II-1, II-2, III-1, and III-9 in this large pedigree are possible male carriers of the autosomal mutation (19).

Imprinted genes are an example of non-Mendelian genetics, in which only one member of the gene pair is expressed and the parent of origin determines expression. To date, nearly 76 imprinted genes have been reported and imprinting mechanism seems to be highly conserved between mice and humans, with only a few of the studied genes not imprinted in both species (www.geneimprint.com).

In summary, we report a large family with the IMAGe association that shares most of the clinical characteristics described previously. It appears that certain minimal clinical differences observed might represent the clinical spectrum of this association. The adrenal deficiency is variable within patients; however, we believe all patients are at high risk of acute adrenal crisis. Consequently, we recommend replacement with corticosteroids in milder forms of adrenal insufficiency. We propose that a possible cause of the IMAGe association in this family could be through a growth-related gene(s) with imprinting mechanisms in association with the anomalous expression of different genes. In addition, the variable expressivities on the phenotype observed in some relatives is compatible with the genomic imprinting mechanism (20). This mode of transmission may have considerable implications for genetic counseling. Furthermore, pediatric endocrinologists must be aware of the possible occurrence of this life-threatening condition in the offspring of nonaffected women when related to a family member with the IMAGe association. However, the apparently independent genetic events as possible mechanism of transmission still remain speculative. We are in the process of performing whole genome linkage analysis to test these hypothesis.

	Acknowledgments

 
The authors thank Mr. Rodolfo De Bellis for help with the preparation of the figures and Dr. Saúl Malozowski for the critical revision of the manuscript and useful suggestions.

	Footnotes

 
This work was supported by the National Research Council of Argentina (Consejo Nacional de Investigaciones Cientificas y Técnicas) PIP865, La Fundación de la Universidad Autónoma de Madrid (proyecto 799000).

First Published Online March 15, 2005

Abbreviations: AHC, Adrenal hypoplasia congenita; DAX1, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1; IMAGe, IUGR, metaphyseal dysplasia, adrenal insufficiency, and genital anomalies; IUGR, intrauterine growth retardation; SDS, SD score; SGA, small for gestational age.

Received August 16, 2004.

Accepted March 4, 2005.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: 90/6/3186    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bergadá, I. Articles by Copelli, S. Search for Related Content PubMed PubMed Citation Articles by Bergadá, I. Articles by Copelli, S. Related Collections Adrenal and Hypertension Calcium and Bone Metabolism Female Endocrinology Male Endocrinology Pediatric Endocrinology