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BRIEF REPORT |
Our Lady’s Children’s Hospital (S.M.P.O., S.A.L., C.C.) and The National Centre for Medical Genetics (S.M.P.O., S.A.L.), Crumlin, Dublin 12, Ireland; Developmental Endocrinology Research Group (S.M.P.O., P.C.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; and Centre for Endocrinology (L.F.C., A.J.L.C.), Barts & London, Queen Mary, University of London, London E1 1BB, United Kingdom
Address all correspondence and requests for reprints to: Stephen O’Riordan, Developmental Endocrinology Research Group, Clinical Molecular Genetics Unit, Level 3, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom. E-mail: s.oriordan{at}ich.ucl.ac.uk.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsDiscussionReferences |
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Aims: The objective of the study was to describe the clinical features and assess the prevalence of FGD amongst Irish Travelers in the Republic of Ireland and describe their phenotype.
Methods: Diagnosis of FGD was based on clinical features, high ACTH, and low cortisol concentrations with normal renin and aldosterone concentrations and exclusion of other causes of adrenal failure. Data from the Republic of Ireland Census 2006 were used.
Results: We identified 21 cases of FGD, generating an overall prevalence of one in 201,898. We report nine Irish Travelers (five females) with FGD related to a new gene negative for melanocortin-2 receptor and melanocortin-2 receptor accessory protein mutations. Of a total population of 22,557 Travelers, this yields a disease prevalence of one in 2506 with a carrier frequency of one in 25 in this group and represents a prevalence of one in 665 and a carrier frequency of one in 13 in the 4- to 15-yr Traveler age group. All nine children had a later onset of FGD due to the fact that their initial investigations revealed normal cortisol (422–575 nmol/liter) and ACTH (<34 ng/liter) concentrations.
Conclusion: We report a high prevalence of FGD among Irish Travelers. Their subtle phenotype and initial normal biochemistry may delay the early diagnosis of FGD.
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Introduction |
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TopAbstractIntroductionPatients and MethodsDiscussionReferences |
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsDiscussionReferences |
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Prevalence
As part of a larger study examining the prevalence of ACTH resistance in Ireland, we estimated prevalence figures for FGD among a genetic isolated community, the Irish Travelers. We used the Republic of Ireland Census of 2006 to provide up-to-date data for estimation of the denominator (12). The total population in the Republic of Ireland at this time was 4,239,848 (12). We identified 21 cases of FGD, generating an overall prevalence of one in 201,898. Another child with FGD type 1 died before this study. All cases were Caucasian, except one child of Sudanese origin.
There were nine cases of FGD among a total population of 22,557 Irish Travelers, yielding a disease prevalence of one in 2,506 and a carrier frequency of one in 25. Subdividing further into the age range of presentation, there are 5989 Irish Travelers aged between 4 and 15 yr, generating a disease prevalence in this age range of one in 665.
Presentation
Eight of the nine cases presented over the age of 4 yr with mild dysmorphic features and short stature. In the three kindreds from the same Irish Traveler nomadic group, all children presented late and were relatively asymptomatic. Measurement of cortisol and ACTH had been performed at a mean age of 1.0 yr (range 3 months to 2.5 yr) for screening purposes in a high-risk population and was normal in all but one case (Table 1
). Others were screened because of unexplained infant death within the family or a family history of adrenal disease. The majority of these nine children presented with acute childhood illness to a local hospital. Initial clinical symptoms included hypoglycemia in six of nine (67%); failure to thrive in seven of nine (78%); and hyperpigmentation in eight of nine (90%).
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Later biochemical analysis at a mean age of 5.3 yr (range 4.4–8.5 yr) was abnormal and typical of classic FGD. All cases were commenced on hydrocortisone replacement therapy at a median dose 12.8 mg/m2·d (range 10–15 mg/m2·d) and remain on replacement therapy. ACTH concentrations remained high despite standard glucocorticoid replacement therapy in all nine cases.
One child had screened positive (using mitomycin C) for a diagnosis of mosaic Fanconi anemia. Fanconi anemia is common among Irish Travelers and a common homozygous deletion of exons 11–14 in the FANCA gene has been identified (13). However, he tested negative for this mutation and has not developed the typical hematological signs of the condition at age 10 yr, nor has he the typical malformations, suggesting alternative mechanisms of chromosomal breakage. Low normal natural killer (NK) cells were observed in three cases but all were well. The other patients had normal NK levels and their growth parameters were not dissimilar. Excess endogenous glucocorticoids affect spontaneous NK cell activity, and exogenous administration may have the same effect; (14); however, none of the Irish Traveler children were on excess glucocorticoid therapy.
Non-MC2R/MRAP mutations in Irish Traveler children
The nine affected children come from three separate clans. Extensive pedigree analysis has not yet revealed a common ancestor. However, affected individuals from all three clans had normal MC2R and MRAP sequencing, and it is likely that they have a common mutation in an as-yet-unidentified gene. Other causes of adrenal insufficiency, adrenoleukodystrophy, congenital adrenal hyperplasia, AAA syndrome (Alarcrima, Achalasia, and Adrenal insufficiency), and Addison’s disease were excluded.
Phenotype and growth
There were some minor dysmorphic facial features common to all nine cases in the Irish Traveler group including a thin upper lip, cupids bow lip, prominence of the forehead, and mild (Fig. 1) or severe hyperpigmentation [eight of nine (90%)]. This evolved into a picture of late-presenting adrenal insufficiency with subsequent short stature on standard replacement hydrocortisone doses (10–15 mg/m2·d).
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). The current heights are –1 to –2 SD below the expected midparental height. This was on standard replacement hydrocortisone doses (10–15 mg/m2·d). Most growth profiles slowed down after glucocorticoid replacement therapy started, and some continued to grow poorly, irrespective of target centiles. Many cases had their hydrocortisone reduced to less than standard glucocorticoid replacement therapy to exclude any growth-inhibiting effect. One patient had daily hydrocortisone withdrawn for 5 months, with no catch-up growth documented. |
Discussion |
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TopAbstractIntroductionPatients and MethodsDiscussionReferences |
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Irish Travelers are an endogamous nomadic group. There are 22,557 Irish Travelers in the Republic of Ireland (12). Another 1710 Irish Travelers live in Northern Ireland (15), and it is estimated that there are approximately 5000 on the mainland United Kingdom, with a similar number residing in mainland Europe (15). More than 59 autosomal recessive conditions are known in this community including 19 inborn errors of metabolism (16). A recent paper reported 23% of Irish Travelers marry first cousins (17). Second-cousin marriage would also be very common, although there are no recent figures available. Anecdotally the majority of Irish Travelers marry within their family with only a small percentage marrying outside the community. These nine FGD children came from three separate clans within the Irish Traveler community. Despite drawing a detailed three-generation pedigree analysis, we were unable to link the three families. All these children were from first cousin marriages.
Most descriptions of FGD highlight early-onset presentation (<5 yr), often with tall stature; however, in the patients from the IT group, six of nine (67%) were SGA and remained small at presentation. Ninety percent (eight of nine) presented late and showed significant hyperpigmentation. All cases had been tested (intercurrent illness or family screen) initially and were normal at a mean of 1.0 yr (range 3 months to 2.5 yr) before eventual clinical presentation. The fact that initial biochemical testing was normal in all cases (Table 1) delayed the diagnosis of FGD. This emphasizes the need to revisit the possibility of the diagnosis of FGD in the absence, at present, of a definitive genetic test(s). Although the biochemistry appeared normal initially, later biochemical analysis was typical of cases presenting with FGD types 1 or 2. The slowly evolving FGD in the IT group may imply a degenerative process of the adrenal cortex. This has been described in isolated cases in MC2R, with one child presenting as late as 9 yr old (Clark, A. J., personal communication). However, all cases in this series are normal for the MC2R mutation on sequencing analysis.
All cases were commenced on hydrocortisone replacement therapy at a median dose 12.8 mg/m2·d and remained on replacement therapy for a median age 5.3 yr (range 4.1–8.5 yr). Despite standard replacement therapy, the final height was below expectation in contrast to type 1 FGD patients, who have a mean height above normal. The heights in children with MRAP (FGD2) have not been reported. All nine of our IT patients fell below expected midparental height and six of nine (67%) were –1.1 to –2.0 SDS below mean height. Whether this suggests an enhanced sensitivity to glucocorticoids, a statural abnormality associated with FGD in this population, or another growth-restricting abnormality in this inbred population remains unclear at present.
It has been suggested that height velocity is faster in the absence of normal endogenous glucocorticoid and slows with the introduction of replacement therapy. This was considered in all nine patients with poor height velocity and poor final height, who were tried on low glucocorticoid replacement doses with none greater than 15 mg/m2·d.
Conclusions
We describe the prevalence of a new variant of FGD in the Irish Traveler subpopulation. The variant condition differs from that seen in patients with types 1 and 2 FGD with later presentation but SGA at birth and normal initial biochemistry. We have also estimated minimum prevalence figures for FGD among the general population in the Republic of Ireland. We recommend considering a diagnosis of FGD in children from this community who present with SGA, hypoglycemia, and hyperpigmentation. In those with a family history of FGD, until the genetic mutation is identified, we recommend clinical follow-up with instructions for the family to seek medical advice during intercurrent illness. We await final gene mapping to locate the gene locus specific to FGD in the Irish Traveling community (16).
Contributions
The study was designed by Stephen O’Riordan, Sally-Ann Lynch, and Colm Costigan. It was undertaken by Stephen O’Riordan, and all authors contributed to analysis of the data and writing of the manuscript. All authors had access to all data in the study and the responsibility for the decision to submit for publication was a joint one.
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Acknowledgments |
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Footnotes |
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First Published Online April 22, 2008
Abbreviations: FGD, Familial glucocorticoid deficiency; MC2-R, melanocortin-2 receptor; MRAP, MC2-R accessory protein; NK, natural killer; SDS, SD score; SGA, small for gestational age.
Received January 7, 2008.
Accepted April 4, 2008.
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References |
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