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Congenital adrenal hyperplasia in a child with 47, XYY: Case report

      Introduction

      Dual genetic diagnoses requiring endocrine surveillance represents an unusual clinical scenario. We present an interesting case of a 4 year 3-month-old male who was diagnosed with 21-hydroxylase insufficiency and a sex chromosome trisomy of 47, XYY. The child was born at 37 weeks gestation to a 29-year-old mother who conceived using in virto fertilization. Pregnancy was uncomplicated until the third trimester when oligohydramnios was diagnosed and the birth was induced. Mother underwent noninvasive prenatal screening that suggested sex chromosome aneuploidy. The parents declined further pre-natal testing and opted for confirmatory testing after birth. Following birth, cytogenetic testing confirmed the diagnosis of 47, XYY. Newborn screening identified the additional diagnosis congenital adrenal hyperplasia, salt-wasting type. Initially lethargic and slow to feed the child improved on a course of fludrocortisone and hydrocortisone. The child has done well with the CAH with the exception of two adrenal crisis episodes from which he recovered well. The child underwent orchiopexy to repair an undescended testis age 18 months of age. At his current age, his weight is in the 11th percentile and height in the 14th percentile. The historical growth curve has been steady in these percentiles. Recent bone age study based on the Greulich and Pyle standard revealed a bone age of 1 year and 6 months.

      Background

      47, XYY is a sex chromosome trisomy that occurs in approximately 1 in 1000 male births. The phenotype associated with this trisomy includes tall stature, macrocephaly, macroorchidism, hypotonia and tremor (
      • Bardsley M.Z.
      • Kowal K.
      • Levy C.
      • Gosek A.
      • Ayari N.
      • Tartaglia N.
      • Lahlou N.
      • Winder B.
      • Grimes S.
      • Ross J.L.
      47,XYY syndrome: clinical phenotype and timing of ascertainment.
      ;
      • Ross J.L.
      • Roeltgen D.P.
      • Kushner H.
      • Zinn A.R.
      • Reiss A.
      • Bardsley M.Z.
      • McCauley E.
      • Tartaglia N.
      Behavioral and social phenotypes in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome.
      ;
      • Urbanus E.
      • Swaab H.
      • Tartaglia N.
      • Cordeiro L.
      • van Rijn S.
      The behavioral profile of children aged 1–5 years with sex chromosome trisomy (47,XXX, 47,XXY, 47,XYY).
      ).This trisomy is also associated with normal to low-normal IQ, learning disabilities, language delay and increased risk for behavioral problems, attention hyperactivity deficit disorder (ADHD) and autism spectrum disorder (
      • Bardsley M.Z.
      • Kowal K.
      • Levy C.
      • Gosek A.
      • Ayari N.
      • Tartaglia N.
      • Lahlou N.
      • Winder B.
      • Grimes S.
      • Ross J.L.
      47,XYY syndrome: clinical phenotype and timing of ascertainment.
      ;
      • Ross J.L.
      • Roeltgen D.P.
      • Kushner H.
      • Zinn A.R.
      • Reiss A.
      • Bardsley M.Z.
      • McCauley E.
      • Tartaglia N.
      Behavioral and social phenotypes in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome.
      ;
      • van Rijn S.
      A review of neurocognitive functioning and risk for psychopathology in sex chromosome trisomy (47,XXY, 47,XXX, 47, XYY).
      ). While formally understood that males with a supernumerary Y would have robust testicular function, current evidence suggests that non-obstructive azoospermia and hypogonadism is more widely seen and that this may impact biologic reproduction (
      • Boroujeni P.
      • Sabbaghian M.
      • Vosough Dizaji A.
      • Zarei Moradi S.
      • Almadani N.
      • Mohammadpour Lashkari F.
      • Zamanian M.R.
      • Mohseni Meybodi A.
      Clinical aspects of infertile 47,XYY patients: a retrospective study.
      ;
      • Flannigan R.
      • Schlegel P.N.
      Genetic diagnostics of male infertility in clinical practice.
      ;
      • Kim I.W.
      • Khadilkar A.C.
      • Ko E.Y.
      • Sabanegh Jr., E.S.
      47,XYY Syndrome and male infertility.
      ).
      Congenital Adrenal Hyperplasias (CAH) are a rare group of genetic conditions that cause disruption in adrenal steroidogenesis (
      • Claahsen-van der Grinten H.L.
      • Speiser P.W.
      • Ahmed S.F.
      • Arlt W.
      • Auchus R.J.
      • Falhammar H.
      • Flück C.E.
      • Guasti L.
      • Huebner A.
      • Kortmann B.B.M.
      • Krone N.
      • Merke D.P.
      • Miller W.L.
      • Nordenström A.
      • Reisch N.
      • Sandberg D.E.
      • Stikkelbroeck N.M.M.L.
      • Touraine P.
      • White P.C.
      Congenital adrenal hyperplasia-current insights in pathophysiology, diagnostics, and management.
      ;
      • Speiser P.W.
      Congenital adrenal hyperplasia.
      ;
      • Speiser P.W.
      • Arlt W.
      • Auchus R.J.
      • Baskin L.S.
      • Conway G.S.
      • Merke D.P.
      • HFL M.-B.
      • Miller W.L.
      • Murad M.H.
      • Oberfield S.E.
      • White P.C.
      Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline.
      ;
      • Witchel S.F.
      Congenital Adrenal Hyperplasia.
      ). The most common form of CAH is due to 21-hydroxylase deficiency occurring in approximately 1 in 15,000 births. Several genetic mutations account for varying levels of the enzyme that produces a spectrum of effects. Two subcategories exist for this form of CAH; Classic and Non-Classic. The Classic form of CAH may be further divided into salt-wasting type or the simple virilizing type. Classic CAH is the most severe form that requires careful surveillance to prevent adrenal crisis that could lead to death if untreated. The Non-classic form is much milder that may not present symptoms at all. Treatment for CAH is usually composed of daily adminstration of glucocorticoid and mineralcorticoid supplements. The typical dosing schedule for these medications, however, do not replicate the circadian pattern of a healthy adrenal cortex that may lead to over-treatment or under-treatment intermittently contributing to growth suppression in children (
      • Speiser P.W.
      Emerging medical therapies for congenital adrenal hyperplasia.
      ).

      Discussion

      Tall stature in sex chromosome trisomies has been attributed to triplicate expression of the short stature homeobox-containing gene (SHOX) located on the distal ends of Xp and Yp (
      • Stochholm K.
      • Juul S.
      • Gravholt C.H.
      Socio-economic factors affect mortality in 47,XYY syndrome-A comparison with the background population and Klinefelter syndrome.
      ). The growth trajectory of a child with 47 XYY is typically follows a usual curve in early life until puberty when growth accelerates exceeding the midparental target (
      • Aksglaede L.
      • Jensen R.B.
      • Carlsen E.
      • Kok P.
      • Keenan D.M.
      • Veldhuis J.
      • Skakkebaek N.E.
      • Juul A.
      Increased basal and pulsatile secretion of FSH and LH in young men with 47,XXY or 46,XX karyotypes.
      ;
      • Ratcliffe S.
      Long-term outcome in children of sex chromosome abnormalities.
      ). The child in this report is showing early evidence of growth delay that may be iatrogenic due to factors intrinsic to his treatment for CAH. Treatment for CAH using steroid medications represent a tightrope of consequences. If a child is under-treated, they are at risk of a potentially life-threatening adrenal crises and if they are overtreated, linear growth may be affected as well as the development of truncal obesity and osteopenia (
      • Bachelot A.
      • Chakhtoura Z.
      • Samara-Boustani D.
      • Dulon J.
      • Touraine P.
      • Polak M.
      Bone health should be an important concern in the care of patients affected by 21 hydroxylase deficiency.
      ). A recent study by Hoyer-Kuhn et al. on hydrocortisone dosing in children with CAH from a German/Austrian registry showed that a high proportion of children were being treated with hydrocortisone doses higher than recommended (
      • Hoyer-Kuhn H.
      • Huebner A.
      • Richter-Unruh A.
      • Bettendorf M.
      • Rohrer T.
      • Kapelari K.
      • Riedl S.
      • Mohnike K.
      • Dörr H.-G.
      • Roehl F.-W.
      • Fink K.
      • Holl R.W.
      • Woelfle J.
      Hydrocortisone dosing in children with classic congenital adrenal hyperplasia: results of the German/Austrian registry.
      ). This gives us pause to consider re-evaluation of CAH treatment as the child's body surface area changes by age. The current guideline from the Endocrine Society recommends that for growing children, maintenance therapy with hydrocortisone be calculated at 10–15 mg/m2 (
      • Speiser P.W.
      • Arlt W.
      • Auchus R.J.
      • Baskin L.S.
      • Conway G.S.
      • Merke D.P.
      • HFL M.-B.
      • Miller W.L.
      • Murad M.H.
      • Oberfield S.E.
      • White P.C.
      Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline.
      ).
      While this case may be unusual, it illustrates important complexities surrounding the interplay of biologic and exogenous supplementation of hormones in a growing child. Of additional consideration for this child is whether he will be eugonadal or hypogonadal with respect to testosterone production as he approaches and progresses through puberty. The addition of supplemental testosterone, if required, and its dosing must be considered carefully with its potential to influence the treatment for CAH and its other effects on health. At this child's age, it is difficult to predict how the supernumerary Y in his karyotype will influence his growth, pubertal progression or gonadal status. The CAH diagnosis in this child is serious and its treatment must take precedence among the other health concerns. This case illustrates the importance of careful endocrine surveillance in a child with overlapping and complex genetic conditions involving the endocrine system.

      Implications

      Pediatric endocrine nurses are often the first to recognize and connect important hormonal benchmarks and trends when caring for children. Anticipation of immediate and future health needs is a central skill for nurses to assure adequate surveillance and management of children who navigate complicated endocrine conditions and circumstances.

      Declaration of Competing Interest

      The authors have no conflicts of interest to disclose.

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