Cécile Brachet

Children’s virilization and the use of a testosterone gel by their fathers

We report severe virilization in three unrelated children by contact with their fathers, who had been using a testosterone lipogel.

Association of parathyroid adenoma and familial hypocalciuric hypercalcaemia in a teenager

OBJECTIVEnFamilial hypocalciuric hypercalcaemia (FHH) is clinically characterized by mild to moderate parathyroid hormone (PTH)-dependent hypercalcaemia, autosomal dominant pattern of inheritance, and normal to frankly reduced urinary calcium excretion in spite of a high serum calcium (clearance (Ca)/clearance (Cr)<0.01). FHH has a benign course and should be differentiated from primary hyperparathyroidism. It is usually caused by a heterozygous loss-of-function mutation in the calcium-sensing receptor gene (CASR).nnnDESIGNnWe report the case of a 16-year-old patient with hypercalcaemia and a mixed family history of parathyroid adenoma and mild hypercalcaemia. Serum calcium was 14 mg/dl with a serum iPTH of 253 pg/ml.nnnRESULTSnA neck 99mTc-sesta MIBI tomoscintigraphy showed a definite hyperactivity in the left upper quadrant. A surgical four-gland exploration confirmed a single parathyroid adenoma. After surgical resection of a left superior parathyroid adenoma, the patients hypercalcemia improved but did not normalize, returning to a level typical of FHH. An inactivating mutation in exon 4 of the CASR gene, predicting a p.Glu297Lys amino acid substitution was found.nnnCONCLUSIONSnThus, this 16-year old patient presented with the association of FHH and a single parathyroid adenoma. The young age of the patient and the association of parathyroid adenoma and FHH in his grandmother argue for a causal link between CASR mutation and parathyroid adenoma in this family. This case contributes to illustrate the expanding clinical spectrum of CASR loss-of-function mutations.

Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports.

Background: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a disorder of water balance linked to gain-of-function mutation of arginine vasopressin receptor type 2 (AVPR2) resulting in free water reabsorption and episodes of hyponatremia. Aims: To review the long-term treatment of NSIAD. Methods: In the first part of this paper, we report 3 cases of male patients presenting with hyponatremia due to NSIAD. The second part consists of a comprehensive review of all published case reports. Results: In our experience, long-term fluid restriction (FR) and treatment with low doses of urea are efficient and well tolerated. Episodic intake of urea seems sufficient in some patients. Treatment data were available for 13 of the 16 hyponatremic patients reported in the literature. Each of these 13 patients had regulated fluid intake. Six of the patients received urea with no reported failure to correct hyponatremia and 5 received NaCl supplementation with varying efficacy. The AVPR2 antagonists tolvaptan and satavaptan (prescribed before the diagnosis of NSIAD was made) showed no efficacy in 1 patient. Conclusions: NSIAD is quite easy to treat with FR and urea in adults as well as in children, with good compliance and efficacy. Of note, FR is well tolerated, suggesting that NSIAD may differ from other causes of syndrome of inappropriate antidiuretic hormone secretion by reduction of thirst intensity due to lower levels of AVP (which stimulates thirst). In eventual refractory cases, furosemide (associated with NaCl supplementation) would represent a valuable therapeutic option by analogy of its efficacy in syndrome of inappropriate antidiuretic hormone secretion.

Symptomatic Heterozygotes and Prenatal Diagnoses in a Nonconsanguineous Family with Syndromic Combined Pituitary Hormone Deficiency Resulting from Two Novel LHX3 Mutations

CONTEXTnOnly 11 mutations have been reported in the transcription factor LHX3, known to be important for the development of the pituitary and motor neurons. All patients were homozygous, with various syndromic forms of combined pituitary hormone deficiency (CPHD), hampering to allocate, in these consanguineous patients, the respective contribution of LHX3 and additional genes to each symptom.nnnOBJECTIVEnThe aim of the study was to report the family history and the molecular basis of a nonconsanguineous patient with syndromic CPHD.nnnPATIENTnThe patient, who presented at birth with respiratory distress, had a syndromic CPHD, including severe scoliosis, and normal intelligence. His father and paternal grandmother displayed limited head rotation.nnnRESULTSnTwo new LHX3 defects were identified. The paternally inherited c.252-3C>G mutation, which disrupts an acceptor splice site, would lead to severely truncated proteins containing a single LIM domain, resembling LIM-only proteins. Coexpression studies revealed the dominant-negative effect of this LIM-only protein over the wild-type LHX3. The maternally inherited p.Cys118Tyr mutation results in partial loss of transcriptional activity and synergy with POU1F1. Given the severity of the patients phenotype, two prenatal diagnoses were performed: the first led to pregnancy interruption, the second to the birth of a healthy boy.nnnCONCLUSIONSnThis study of the first nonconsanguineous patient with LHX3 mutations demonstrates the pleiotropic roles of LHX3 during development and its full involvement in the complex disease phenotype. Isolated limitation of head rotation may exist in heterozygous carriers and would result from a dominant-negative effect. These data allowed the first prenatal diagnoses of this severe condition to be performed.

Hearing loss is part of the clinical picture of ENPP1 loss of function mutation

Background: Ecto/nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) loss-of-function mutations have been described in patients with autosomal recessive hypophosphatemic rickets (HR), in patients with generalized arterial calcification of infancy (GACI) and in several patients with both conditions. Out of more than 50 cases of homozygous or compound heterozygous ENPP1 loss-of-function mutations published so far, 1 case with labyrinthine deafness probably due to occlusion of inner ear supplying arteries and 2 cases of conductive hearing loss due to stapedovestibular calcification diagnosed in childhood have been reported. Aims: To report a case of ENPP1 loss-of-function novel mutation presenting with HR and very early onset and severe hearing loss. Methods: Case report and review of the literature. Results: We report on a patient homozygous for a novel 1-bp deletion in ENPP1 that presented with GACI evolving towards HR associated with a mixed hearing loss (both labyrinthine and conductive) diagnosed at 9 days of life that evolved towards profound labyrinthine deafness. Conclusion: Hearing loss is a rare finding in patients with ENPP1 loss-of-function mutations. Interestingly, it has already been described in other affected patients, in ENPP1 knock-out mice and in other diseases of pyrophosphate metabolism. Conversely it seems to be absent in children with the X-linked form of HR.

Nephrogenic syndrome of inappropriate antidiuresis in a female neonate: Review of the clinical presentation in females

Background: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare X-linked disease due to gain-of-function mutations in the AVP V2 receptor gene. Hemizygous males present with recurrent episodes of severe hyponatremia in infancy. Heterozygous females are usually asymptomatic. Case Report: We report on a 23-day-old female neonate, born at term with 3,260 g that presented with recurrent hyponatremia (Na between 124 and 134 mmol/l) due to NSIAD. She was a heterozygous carrier of the c.409 C>T mutation in the AVPR2 gene. Conclusions: This is the first report of a female neonate presenting with hyponatremia due to NSIAD. The diagnosis of NSIAD should not be limited to male infants and should also be considered in female infants with the clinical picture of inappropriate antidiuresis.

Central precocious puberty after interpersonal transfer of testosterone gel: just a coincidence?

Abstract Background: Over the last 10 years, several children, fetuses and women have been reported to be virilized through interpersonal transfer of testosterone (T) gel used by fathers or partners. Long-term exposure to androgens in children, such as in poorly controlled congenital adrenal hyperplasia, is known to promote central precocious puberty. Methods: Clinical case report. Results: We report on a 5-year-old boy who developed central precocious puberty after long-term (starting prenatally) exposure to testosterone through interpersonal transfer of T gel used by his father. We also report on another case illustrating that the recommended precautions are not sufficient to avoid interpersonal transfer of T gel among household contacts. Plasma testosterone levels and history-taking revealed the cause of virilisation and the testosterone contamination source in both cases. Given the increased testicular volume and persisting testosterone elevation after cessation of gel use in the first patient, a GnRH test was carried out and confirmed central precocious puberty. Conclusion: This is the first report of a boy with central precocious puberty occurring after long-term (starting prenatally) exposure to testosterone through the interpersonal transfer of T gel. This report questions whether central precocious puberty constitutes a long-term side effect of testosterone exposure in childhood through T gel use by a household contact.

Congenital Hypothyroidism: Long-Term Experience with Early and High Levothyroxine Dosage

Aim: To assess the management and outcome of the congenital hypothyroidism (CH) patients followed at our institution since the introduction of systemic neonatal screening for CH. Study Design: The records of 139 CH patients referred to our center between 1978 and 2014 were retrospectively reviewed. Biochemical and imaging data at diagnosis, initial treatment and growth were analyzed. Results: 111 patients had thyroid dysgenesis (64 ectopy, 46 athyreosis and 1 hypoplasia) and 28 patients had a gland in situ (17 dyshormonogenesis/goiter and 11 normal-sized gland). Levothyroxine treatment was initiated at a median age of 11 days with a mean dose of 11.4 µg/kg/day. Compared to those with ectopy, patients with athyreosis had higher thyroid-stimulating hormone (TSH) and lower thyroxine at diagnosis as well as more delayed bone maturation. Between 1978 and 2014, we observed earlier treatment and earlier TSH normalization. Birth auxology was slightly above the mean of the reference population. Growth at 1 and 6 years and school progression at 11 years were similar to those of the reference population. Conclusion: Ectopy is the commonest cause of CH. Children with CH treated early with a mean levothyroxine dose of 11.4 µg/kg/day had a median TSH of 3.07 mU/l at 1 month of age and normal growth.