A 14-year-old adolescent with short stature and delayed puberty, was admitted in a Paediatric Endocrinology outpatient clinic. His familial target height was on percentile 3–10. After a careful investigation, he was found to have a 45,X/46,X,idic(Y)(p11.32) mosaicism.
A 14-year-old boy was referred to our Paediatric Endocrinology Center due to short stature. He was the first son of two children, with a healthy sister and irrelevant familial history. Familial target height was on percentile 3–10. Uneventful pregnancy, delivery, and neonatal period were seen. At the age of 5, he was submitted to correction of aortic coarctation and had arterial hypertension diagnosis, beginning treatment with enalapril (follow-up at Cardiology). He had an adequate psychomotor development.
Height growth was on percentile 10–25 until he was 11, with growth deceleration since then. On first appointment with pediatric endocrinology, the patient’s height and growth velocity were below percentile 3. His weight evolution was on percentile 25–50 until the age of 7, with exponential rise afterwards until percentile 97 (body mass index of 31 kg/m2).
At observation, besides height and weight disproportion already mentioned (weight 62 kg and height 141.2 cm), the patient presented round and red face, large and short neck, cervical acanthosis nigricans, well-muscled body, and melanocytic nevus on the back and limbs. Pubertal development: axillary hair present; pubic hair at Tanner stage 2; penis covered by prepubic fat (length 5.5 cm) but normal consistency; and testis in the scrotum, with a bilateral testicular volume of 4 ml3.
Laboratorial and imagiologic evaluation:(i)Blood count, albumin, renal and hepatic function, ionogram, and phosphocalcic metabolism were normal(ii)Lipidic and glucidic profile: total cholesterol 219 mg/dL (reference range: <200 mg/dL), HDL 55 mg/dL (r.r.: >60 mg/dL), LDL 141 mg/dL (r.r.: <130 mg/dL); triglycerides 115 mg/dL (r.r.: <150 mg/dL); HbA1c 5.8%; glucose/insulin ratio 3.7 (low, suggestive of insulin resistance)(iii)Celiac disease: negative anti-gliadin and anti-transglutaminase antibody measurements(iv)Thyroid function was normal(v)Adrenal function evaluation: normal basal 17-hydroxyprogesterone and dehydroepiandrosterone-sulfate for Tanner stage 2. Normal basal and stimulated values for 17-hydroxyprogesterone, 11-deoxycortisol, and delta-4-androstenedione in ACTH stimulation test(vi)IGF-1 and IGFBP3 were normal(vii)Left hand and wrist X-ray: 15-year-old bone age, for a chronologic age of 14 years and 4 months(viii)Renal ultrasound: no anomalies
Considering growth deceleration, arterial hypertension, round and red face, acanthosis nigricans, and hypercholesterolemia, the first hypothesis was hypercortisolism. However, 24 h urinary cortisol was normal (230 μg/24 h, to r.r.: 55.5–286 μg/24 h) as well as overnight 1 mg-dexamethasone suppression test (0.6 mg/dL, to r.r.:<1.8 mg/dL).
Because there was growth deceleration and nonevolving puberty, as well as an advance in the bone age, pituitary-gonadal axis was evaluated: normal prolactin measurement, undetectable gonadotrophins (LH and FSH), and total testosterone determinations, which could be compatible with a prepubertal stage or hypogonadotropic hypogonadism. Cranial magnetic resonance imaging showed no anomalies.
In order to differentiate hypothalamic or pituitary origin for this hypogonadism, the next step should have been the LH-RH test. However, this was not performed as the patient started exogenous testosterone after seeking a second medical opinion.
The patient was then referred for medical genetic evaluation, and a molecular analysis was requested. ArrayCGH (Comparative genomic hybridization, PerkinElmer® CGX-HD 180K, Genoglyphix v3.1) identified a mosaicism involving chromosome Y. This rearrangement was further characterized by karyotype and FISH (fluorescence in situ hybridization) with probes for the SRY and for the X (DXZ1) and Y (DYZ3) centromeric regions (Cytocell©) in the blood and buccal mucosa.
This procedure confirmed the existence of two cell lines:(i)a major line with a single hybridization signal for the chromosome X centromeric region, i.e., with 45 chromosomes and no Y chromosome, present in 72% and 51% of the lymphocytes and oral epithelial cells, respectively.(ii)a minor line with a hybridization signal for chromosome X centromeric region and a double hybridization signal for Y centromeric region compatible with a dicentric chromosome, present in 28% and 49% of the cells of peripheral blood and the oral mucosa, respectively.
To further characterize this rearrangement, an SRY probe was used and a double hybridization signal for the Yp11.3 region was detected, at interphase. At metaphase, this minority line shows only a condensed hybridization signal for the SRY locus on the isodicentric chromosome, confirming the absence of only a small part of the short-arm terminal region distal to Yp11.32. In other words, this line is formed by 46 chromosomes with a structurally modified Y constituted by two long arms and part of the small arm, with loss of short arm terminal region at Yp11.3-idic(Y)(p11.3).
Together with the arrayCGH findings, the patient karyotype was(i)mos 46,X,idic(Y)(p11.3)/45,X.ish idic(Y)(SRY+).nuc ish (DXZ1x1)[300/415]/(DXZ1x1,SRYx2)[115/415].arr[GRCh37] Xp22.33/Yp11.32(296520_1211406)x0∼1,Yp11.32q12(246520_59049419)x0∼1
Considering this mosaicism, a testicular ultrasound (US) was performed with no anomalies detected.
Nowadays, the patient is kept under surveillance in Pediatric Endocrinology, under therapeutics with 200 mg testosterone enanthate (intramuscular) monthly. A secondary sexual characteristics progression was observed: development of axillary and pubic hair and testicular volume growth to 8 ml3. On last appointment, the patient was 68.7 kg and 144.5 cm tall. There has been nutritional and regular physical activity counselling as well as natural vegetable steroid ingestion encouragement in order to control obesity and dyslipidemia.
In the future, it is crucial to maintain follow-up and early detection of potential gonadic alterations, with regular testicular US (there is no consensus on periodicity, but the majority recommends annual evaluation; when in doubt a testicular biopsy should be performed), and preconception genetic counselling.