Glynis Price

Newborn Screening for Congenital Hypothyroidism, Victoria, Australia, 1977-1997. Part 2: Treatment, Progress and Outcome

A controlled longitudinal prospective study is reported of physical and neuropsychological progress up to 12 years in 152 children with congenital hypothyroidism (CH), detected by newborn screening in the Australian state of Victoria and born between the onset of screening in mid-1977 and December 1988. Linear growth of the CH children was normal. Throughout they were slightly heavier and the median head circumference was slightly larger compared with reference data. Those with thyroid aplasia required a marginally larger dose of thyroxine to achieve euthyroidism. Assessment of cognitive outcome in the children with permanent primary CH revealed the mean scores at 2, 5 and 8 years to be from 8.5 (p<0.001) to 10.2 (p<0.001) points lower than in a group of 60 euthyroid controls. However, there was large overlap and, of the affected children, only 10.1% at 2 years, 3.9% at 5 years and 6.8% at 8 years fell more than 2 SD below the means of the euthyroid controls. On univariate analysis, variables shown to have significant correlation with cognitive outcome at 8 years in the CH children were newborn activity, baseline TT4 and FTI, initial T4 dosage, socio-economic classification, maternal age, maternal education and presence of a serious accompanying disorder. On multiple regression analysis, significant variables were baseline bone age, maternal age and education, and presence of a serious accompanying disorder. No single thyroidal or extra-thyroidal variable could be identified to account for the discrepancy between the children with CH and the controls.

Sterile abscess formation associated with depot leuprorelin acetate therapy for central precocious puberty

We describe a case of an 8 year old girl with central precocious puberty. She was commenced on 3 monthly intramuscular depot Leuprorelin acetate therapy, as a result of which she developed sterile abscesses. She was converted to daily subcutaneous Leuprorelin acetate therapy with no recurrence of the abscesses. The possible mechanisms for this reaction are described in the article.

Efficacy of Hydrochlorothiazide and low renal solute feed in Neonatal Central Diabetes Insipidus with transition to Oral Desmopressin in early infancy

BackgroundThe treatment of central diabetes insipidus (DI) with desmopressin in the neonatal period is challenging because of the significant risk of hyponatremia with this agent. The fixed anti-diuresis action of desmopressin and the obligate high fluid intake with milk feeds lead to considerable risk of water intoxication and hyponatremia. To reduce this risk, thiazide diuretics, part of the treatment of nephrogenic DI, were used in conjunction with low renal solute feed and were effective in a single case series of neonatal central DI.AimWe evaluated the efficacy of early treatment of neonatal central DI with hydrochlorothiazide with low solute feed and investigated the clinical indicators for transition to desmopressin during infancy.MethodsA retrospective chart review was conducted at Princess Margaret Hospital, Perth of neonates diagnosed with central DI and treated with hydrochlorothiazide, between 2007 and 2013. Four newborns were identified. Mean sNa and mean change in sNa with desmopressin and hydrochlorothiazide treatment were recorded along with episodes of hyponatremia and hypernatremia. Length and weight trajectories during the first 12 months were assessed.ResultsThe mean change in sNa per day with hydrochlorothiazide and low renal solute feed was 2.5 - 3 mmol/L; on desmopressin treatment, the mean change in sNa was 6.8-7.9 mmol/L. There was one episode of symptomatic hyponatremia with intranasal desmopressin with no episodes of hyponatremia or hypernatremia during treatment with hydrochlorothiazide or following transition to oral desmopressin. Transition to oral desmopressin between 3 to 12 months of age was associated with good control of DI. Following introduction of solids, sNa remained stable but weight gain was slow. This improved following transition to desmopressin in one infant.ConclusionsHydrochlorothiazide with low renal solute feed is a safe and effective treatment option in neonatal central DI. However, transition to desmopressin should be considered early in infancy following initiation of solids to facilitate growth.

NNT Pseudoexon Activation as a Novel Mechanism for Disease in Two Siblings With Familial Glucocorticoid Deficiency

Context: Intronic DNA frequently encodes potential exonic sequences called pseudoexons. In recent years, mutations resulting in aberrant pseudoexon inclusion have been increasingly recognized to cause disease. Objectives: To find the genetic cause of familial glucocorticoid deficiency (FGD) in two siblings. Patients: The proband and his affected sibling, from nonconsanguineous parents of East Asian and South African origin, were diagnosed with FGD at the ages of 21 and 8 months, respectively. Design: Whole exome sequencing was performed on genomic DNA (gDNA) of the siblings. Variants in genes known to cause FGD were assessed for causality. Further analysis of gDNA and cDNA was performed by PCR/RT-PCR followed by automated Sanger sequencing. Results: Whole exome sequencing identified a single, novel heterozygous variant (p.Arg71*) in nicotinamide nucleotide transhydrogenase (NNT) in both affected individuals. Follow-up cDNA analysis in the proband identified a 69-bp pseudoexon inclusion event, and Sanger sequencing of his gDNA identified a 4-bp duplication responsible for its activation. The variants segregated with the disease: p.Arg71* was inherited from the mother, the pseudoexon change was inherited from the father, and an unaffected sibling had inherited only the p.Arg71* variant. Conclusions: FGD in these siblings is caused by compound heterozygous mutations in NNT; one causing pseudoexon inclusion in combination with another leading to Arg71*. Discovery of this pseudoexon activation mutation highlights the importance of identifying sequence changes in introns by cDNA analysis. The clinical implications of these findings include: facilitation of antenatal genetic diagnosis, early institution of potentially lifesaving therapy, and the possibility of preventative or curative intervention.

Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia.

Abstract Hyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous ABCC8 mutation, was not responsive to treatment with maximal doses of diazoxide and subcutaneous daily octreotide, and underwent a near-total pancreatectomy; however, hypoglycaemia persisted. Introduction of sirolimus, an mTOR (mammalian target of rapamycin) inhibitor, obviated the requirement for glucose infusion. Euglycaemia was achieved with no significant adverse events from the drug. Sirolimus therapy was ceased at 13 months of age. No episodes of persistent hypoglycaemia were observed after cessation of sirolimus. This report demonstrates the successful use of sirolimus for persistent hypoglycaemia in the critically ill infant post pancreatectomy. Sirolimus could be considered in patients with severe HH not responsive to conventional medical and surgical therapy. However, the long-term efficacy and safety with this immunosuppressive drug in very young patients are not assured.

Report and review of described associations of Mayer-Rokitansky-Küster-Hauser syndrome and Silver-Russell syndrome

Silver–Russell syndrome (SRS) and Mayer‐Rokitansky‐Küster‐Hauser (MRKH) syndrome are described in isolation. However, their co‐occurrence has only been rarely reported. Here, we present a case report of an adolescent with SRS who was diagnosed with MRKH during the evaluation of primary amenorrhoea. Multiplex ligation‐dependent probe amplification analysis showed a normal methylation pattern and normal dosage at 11p15.5. A PubMed search for all peer‐reviewed publications (original articles and reviews) using the key words Silver–Russell syndrome, Mayer‐Rokitansky‐Küster‐Hauser syndrome, genetics, hypomethylation and reproductive anomalies identified three cases of SRS with MRKH, two of which were associated with significant hypomethylation of the H19 imprinting control region of the 11p15.5 locus. This report highlights the association between SRS and MRKH. The absence of hypomethylation and normal dosage at 11p15.5 suggests these two rare entities share alternative aetiopathogenic mechanisms.

Hypothesis: Persistently elevated hCG causes gestational ovarian overstimulation associated with prolonged postpartum hyperandrogenism in mothers of aromatase-deficient babies.

CONTEXT Aromatase deficiency due to a CYP19A1 defect leads to fetoplacental inability to convert androgens into estrogens. Pregnant mothers experience virilization caused by excess nonaromatized fetal androgens entering the maternal circulation. Biochemical normalization is believed to take place shortly after delivery. OBJECTIVE We report prolonged postnatal hyperandrogenism and enlarged multicystic ovaries in the mother of an affected 46,XX infant and hypothesize a possible pathogenetic mechanism. PATIENTS AND METHODS We investigated the mother on days 12 and 20 after delivery. FSH, LH, T, estradiol (E2), androstenedione (A), dehydroepiandrosterone-sulfate (DHEA-S), and human chorionic gonadotropin (hCG) plasma levels were obtained, and ovarian ultrasonography and magnetic resonance imaging were performed. RESULTS T (1040 ng/dL), A (6940 ng/dL), and E2 (2787 pg/mL) levels were markedly elevated on day 12 after delivery, whereas LH and FSH were suppressed (<0.1 IU/L). On day 20, all hormones had decreased significantly; however, T, A, and E2 still remained 3.5-, 2.2-, and 1.4-fold elevated, respectively, as compared to upper reference values. hCG (18.9 U/L) was still increased. DHEA-S was normal on both occasions. Sonography and magnetic resonance imaging revealed enlarged ovaries, with several cysts up to 4 cm. There was no history of polycystic ovary syndrome. CONCLUSIONS We hypothesize that persistent ovarian overstimulation by hCG had occurred in the mother during pregnancy, leading to prolonged autonomous excess production of androgens during the first weeks after delivery. As a causative mechanism, we propose that gestational hyperandrogenism and hypoestrogenism reduced inhibition of placental GnRH and hCG secretion by progesterone, resulting in persistently elevated hCG.

Structural chromosome disruption of the NR3C2 gene causing pseudohypoaldosteronism type 1 presenting in infancy

Abstract Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance presenting in infancy with renal salt wasting and failure to thrive. Here, we present the case of a 6-week-old baby girl who presented with mild hyponatraemia and dehydration with a background of severe failure to thrive. At presentation, urinary sodium was not measurably increased, but plasma aldosterone and renin were increased, and continued to rise during the subsequent week. Despite high calorie feeds the infant weight gain and hyponatraemia did not improve until salt supplements were commenced. Subsequently, the karyotype was reported as 46,XX,inv (4)(q31.2q35). A search of the OMIM database for related genes at or near the inversion breakpoints, showed that the mineralocorticoid receptor gene (NR3C2) at 4q31.23 was a likely candidate. Further FISH analysis showed findings consistent with disruption of the NR3C2 gene by the proximal breakpoint (4q31.23) of the inversion. There was no evidence of deletion or duplication at or near the breakpoint. This is the first report of a structural chromosome disruption of the NR3C2 gene giving rise to the classical clinical manifestations of pseudohypoaldosteronism type 1 in an infant.

Follicular thyroid carcinoma in a child presenting as autonomously functioning thyroid nodule

Thyroid nodules are uncommon in children (1.5%). However, the incidence of thyroid carcinoma in childhood thyroid nodules (26.4%) is 3-4 folds higher than in adults. Autonomously functioning thyroid nodules (AFTN) or hot nodules account for less than 3% of hyperthyroidism in children and carry a small risk of malignancy (2-5%). The majority of malignant hot nodules are papillary thyroid carcinoma (57.1%) with follicular carcinoma reportedly comprising 36.4% of cases. A search of MEDLINE identified 7 paediatric cases of AFTN harbouring carcinoma. Here we report a child, presenting with hyperthyroidism and subsequently diagnosed with follicular thyroid carcinoma. An 11 year old girl presented with a palpable right sided thyroid nodule and symptoms of hyperthyroidism consisting of tachycardia and anxiety. A thyroid ultrasound showed a solitary, minimally heterogenous nodule on the right, measuring 2.5x1.9x1.6 centimetres. It was hyperechoic to the remainder of thyroid gland and had increased intralesional and perilesional vascularity. A radionuclide scan demonstrated the nodule as hyperfunctioning “hot” nodule with no radiotracer uptake in the rest of thyroid. An ultrasound guided FNAC was performed and features consistent with a follicular neoplasm were identified. She underwent right hemi-thyroidectomy and histopathology was consistent with angioinvasive follicular thyroid carcinoma. No evidence of carcinoma was found in the rest of the thyroid following completion thyroidectomy. Additionally, her head circumference was >98th percentile, a lipoma was present over her sacrum and MRI suggested avascular hamartoma over her right ankle, together raising the possibility of Cowden syndrome. FNAC is warranted in all cases of solid thyroid nodules in children including hot nodules to help define the pathology. If inconclusive, surgical excision of lesion for histopathology should be considered. Familial cancer syndromes, which can include a hamartoma/tumour phenotype such as Cowden syndrome and other PTEN hamartoma/tumour syndromes, DICER1 syndrome and MEN2 are also possible, depending on the type of thyroid malignancy. Written informed consent was obtained from the patients parent or guardian for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Sirolimus therapy following subtotal pancreatectomy in neonatal hyperinsulinemic hypoglycaemia: a case report

Hyperinsulinemic hypoglycaemia (HH) occurs due to an unregulated insulin production from the pancreatic β-cells in the presence of low blood glucose. Mutations in ABCC8 and KCNJ11 are associated with severe HH that is unresponsive to conventional medical treatment. The only treatment for patients with medically unresponsive diffuse HH is a subtotal pancreatectomy. However, following surgery, hypoglycaemia may persist and some patients develop diabetes and malabsorption. Overexpression of the mTOR pathway is contributory to HH. Sirolimus, an mTOR inhibitor, is currently used in the treatment of congenital hemangiomas and in post renal transplant. Senniappan et al [1] recently reported efficacy of sirolimus in four surgically naive patients with diffuse HH unresponsive to diazoxide and octreotide. We present a patient who was treated with sirolimus due to persistent hypoglycaemia following subtotal pancreatectomy. A term neonate with a birth weight of 4.67kg had persistent hypoglycaemia since birth secondary to hyperinsulinism and was unresponsive to treatment with maximal doses of diazoxide and octreotide with a glucose infusion requirement (GIR) of 38mg/kg/min. Genetic testing revealed a homozygous ABCC8 nonsense mutation, p.Gln1020Ter. A subtotal pancreatectomy was performed on day 40. Post-surgery, he had a GIR of 20mg/kg/min and was recommenced on daily subcutaneous (SC) octreotide, with monthly long acting (LA) octreotide. At 3 months, he was commenced on oral sirolimus. The dose was adjusted to maintain serum trough levels between 5 and 15ng/ml. Parenteral fluids and SC octreotide were weaned over a month. He was discharged home at 4.5 months on sirolimus (2.5mg/m2/day) and LA octreotide. He was monitored with capillary blood glucose testing twice a day with the aim to maintain levels above 3.5mmol/L. Further surgery has been deferred. His growth and development are appropriate at 6 months of age with no side effects from sirolimus. The clinical response in our patient supports sirolimus as a new therapeutic strategy in patients with HH which may facilitate deferment of surgery. Written informed Consent for this patient has been taken including results of the genetic analyses and histopathological images according to the Institutional Ethics Committee procedures of our health service