Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis.

CONTEXT: SHOX mutations have been detected in approximately 70% of Léri-Weill dyschondrosteosis (LWD) and approximately 2.5% of idiopathic short stature (ISS) cases, suggesting the implication of other genes or loci. The recent identification of NPR2 mutations in ISS suggested that NPR2 mutations may also be involved in disproportionate short stature. OBJECTIVE: The objective of the study was to investigate whether NPR2 mutations can account for a proportion of the cases referred for LWD and ISS in whom no SHOX mutation was detected. PATIENTS AND METHODS: We undertook NPR2 mutation screening in 173 individuals referred for suspected LWD and 95 for ISS, with no known defect in SHOX or its enhancers. Intracellular localization and natriuretic peptide precursor C-dependent guanylate cyclase activity were determined for the identified NPR2 variants. RESULTS: Eight NPR2 variants were identified in nine individuals, seven referred for suspected LWD and two for ISS. Six were demonstrated to affect NPR-B cell trafficking and/or its ability to synthesize cyclic GMP (cGMP) under response to natriuretic peptide precursor C/brain natriuretic peptide stimulation. All pathogenic mutations were detected in the suspected LWD referral group (∼3%). Interestingly, one of these patients is currently being treated with recombinant human GH and in contrast to previous reports is showing a positive response to the treatment. CONCLUSIONS: NPR2 mutations account for approximately 3% of patients with disproportionate short stature and/or clinical or radiographic indicators of SHOX deficiency and in whom no SHOX defect has been identified. However, no patient has yet presented with Madelung deformity. Thus, NPR2 should be screened in the SHOX-negative LWD referrals.

Individualised vs fixed dose of oral 17ß-oestradiol for induction of puberty in girls with Turner syndrome: an open-randomised parallel trial.

CONTEXT: Oestrogen induction of pubertal changes in Turner girls may reinforce their psychological well-being and may also optimise final height; however, oestrogen type, dose, and route are not well established. OBJECTIVE: To induce normal pubertal development in Turner girls and ovarian insufficiency with oral 17ß-oestradiol (E(2)), either as individualised dose (ID) or as fixed dose (FD), and to determine whether growth is affected. DESIGN: Open-label randomised, parallel groups, multicentre clinical trial in 48 GH-treated Turner girls. Oral E(2) was given in tablets, either as an ID of 5-15 µg/kg per day during 2 years or as a FD of 0.2 mg daily during the first year followed by 0.5 mg daily during the second year. Main outcome measures were the event of attaining a Tanner breast staging ≥4 (primary), FSH, and auxological variables (secondary). RESULTS: Shorter median time to Tanner staging ≥ B4 in the FD group (733 days) compared with the ID group (818 days) (P=0.046). Higher proportion of girls with Tanner staging ≥ B4 (65%) in the FD group compared with the ID group (42%) (P=0.068). Bone age did not show inadequate acceleration and adult height prediction was maintained in both groups. No oestrogen-related adverse events were reported. CONCLUSIONS: Two-year treatment with oral E(2) can progressively induce normal pubertal development in Turner syndrome. Low-dose oral E(2) given as a FD produces a satisfactory pubertal development not inferior to ID. Treatment was well tolerated and did not interfere with the growth-promoting effect of GH.

Surgical treatment of persistent hyperinsulinemic hypoglycemia (PHH) (insulinoma and nesidioblastosis).

BACKGROUND: The persistent hyperinsulinemic hypoglycemia is characterized by clinical symptoms that occur when the blood glucose levels drop below the normal range. Two pathological situations cause this clinical problem: The presence of a tumor of the pancreas secreting excessive amounts of insulin, known as insulinoma, and congenital beta-cell hyperplasia in the pancreas in children and noninsulinoma pancreatogenic hypoglycemia syndrome in adults. PATIENTS AND METHODS: Clinical characteristic and surgical outcome of a group of 20 patients operated on for this hypoglycemic syndrome; 18 for insulinoma and two for nesidioblastosis in children was studied. RESULTS: eight of the insulinomas were in the head of the pancreas, two in the body, and the remaining eight in the tail. The surgical technique was enucleation in nine cases, local resection in one case because of suspicious malignancy, and distal pancreatectomy in eight cases. Both children with nesidioblastosis underwent 85% pancreatectomy with splenic preservation. There was no mortality in the study, but three patients developed a low-volume pancreatic fistula after head enucleation. CONCLUSIONS: Negative results in diagnostic localization together with the small size of the insulinoma represent a poor combination for successful surgery. The intraoperative ultrasonography is the method of choice for the identification of the tumor, as it is able to identify nonpalpable lesions.

Neonatal salt-wasting and 11 beta-hydroxylase deficiency in a child carrying a homozygous deletion hybrid CYP11B2 (aldosterone synthase)-CYP11B1 (11 beta-hydroxylase).

This article reports the case of a boy diagnosed at 1.8 years of age with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. The patient showed salt-wasting episodes during the neonatal period. On molecular analysis, a homozygous deletion hybrid (CYP11B2-CYP11B1) involving the CYP11B locus at 8q24.3 was found. Southern blot analysis showed the break point of the chimera gene to be located before intron 5; sequence analysis identified it at exon 4 between codons 202 and 248. This CYP11B2(5')/B1(3') hybrid should lack aldosterone synthase activity (due to the CYP11B1 residues at exons 5 and 6), and the enzyme it codes for should not be promoted by adrenocorticotropic hormone (ACTH) (CYP11B2 promoter sequences). The patient phenotype - neonatal salt-wasting and 11 beta-hydroxylase deficiency - is in agreement with this hybrid structure. This is the first time a homozygous deletion hybrid generated by unequal crossover has been described in exon 4. This genetic lesion appears to be the reciprocal product from the recombination event that causes glucocorticoid-remediable aldosteronism, a duplication dominant allele (CYP11B2-CYP11B1/B2-CYP11B1) coding for additional aldosterone synthase activity regulated by ACTH. The clinical presentation of the condition in this patient contributes to the in vivo understanding of the regulation of this complex locus in which two 'duplicated' genes have evolved different regulatory and enzymatic activities involved in mineralocorticoid and glucocorticoid synthesis in the adrenal glands. The fact that this allele was first predicted and has now been documented clinically and molecularly in vivo is particularly noteworthy.