Dehydroepiandrosterone (DHEA) sulfotransferase, known as SULT2A1, converts the androgen precursor DHEA to its inactive sulfate ester, DHEAS, thereby preventing the conversion of DHEA to an active androgen. SULT2A1 requires 3′-phosphoadenosine-5′-phosphosulfate (PAPS) for catalytic activity. We have identified compound heterozygous mutations in the gene encoding human PAPS synthase 2 (PAPSS2) in a girl with premature pubarche, hyperandrogenic anovulation, very low DHEAS levels, and increased androgen levels. In vitro coincubation of human SULT2A1 and wild-type or mutant PAPSS2 proteins confirmed the inactivating nature of the mutations. These observations indicate that PAPSS2 deficiency is a monogenic adrenocortical cause of androgen excess.

Tpit is a T box transcription factor important for terminal differentiation of pituitary proopiomelanocortin-expressing cells. We demonstrated that human and mouse mutations of the TPIT gene cause a neonatal-onset form of congenital isolated ACTH deficiency (IAD). In the absence of glucocorticoid replacement, IAD can lead to neonatal death by acute adrenal insufficiency. This clinical entity was not previously well characterized because of the small number of published cases. Since identification of the first TPIT mutations, we have enlarged our series of neonatal IAD patients to 27 patients from 21 unrelated families. We found TPIT mutations in 17 of 27 patients. We identified 10 different TPIT mutations, with one mutation found in five unrelated families. All patients appeared to be homozygous or compound heterozygous for TPIT mutations, and their unaffected parents are heterozygous carriers, confirming a recessive mode of transmission. We compared the clinical and biological phenotype of the 17 IAD patients carrying a TPIT mutation with the 10 IAD patients with normal TPIT-coding sequences. This series of neonatal IAD patients revealed a highly homogeneous clinical presentation, suggesting that this disease may be an underestimated cause of neonatal death. Identification of TPIT gene mutations as the principal molecular cause of neonatal IAD permits prenatal diagnosis for families at risk for the purpose of early glucocorticoid replacement therapy.

GH treatment is effective in improving height in short children born small for gestational age (SGA). GH is thought to have limited effect when started during adolescence. The aim of this study was to investigate GH treatment efficacy in short SGA children when treatment was started during adolescence; to assess whether GH 2 mg/m(2) · d during puberty improves adult height (AH) compared with 1 mg/m(2) · d; and to assess whether an additional 2-yr postponement of puberty by GnRH analog (GnRHa) improves AH in children who are short at the start of puberty (<140 cm), with a poor AH expectation. In this longitudinal, randomized, dose-response GH trial, we included 121 short SGA children (60 boys) at least 8 yr of age. We performed intention-to-treat analyses on all children and uncensored case analyses on 84 children who reached AH. Besides, we evaluated growth during 2 yr of combined GH/GnRHa and subsequent GH treatment until AH in a subgroup of 40 pubertal children with a height of less than 140 cm at the start. Short SGA children started treatment at a median age of 11.2 yr, when 46% had already started puberty. Median height increased from -2.9 at start to -1.7 sd score (SDS) at AH (P < 0.001). Treatment with GH 2 vs. 1 mg/m(2) · d during puberty resulted in significantly better AH (P = 0.001), also after correction for gender, age at start, height SDS at start, treatment years before puberty, and target height SDS. AH was similar in children who started puberty at less than 140 cm and received GH/GnRHa, compared with children who started puberty greater than 140 cm and received GH only (P = 0.795). When started in adolescence, GH treatment significantly improves AH in short SGA children, particularly with GH 2 mg/m(2) · d during puberty. When SGA children are short at the start of puberty, they can benefit from combined GH/GnRHa treatment.

Context: Noonan syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. Short-term effect of GH therapy in NS is beneficial, reports on the effect on adult height are scarce.Objective: To determine the effect of long-term GH therapy in children with NS.Design: Twenty-nine children with NS were treated with GH until final height was reached.Setting: Hospital endocrinology departments.Patients: Children with the clinical diagnosis of NS, with mean age at the start of therapy of 11.0 years, 22 out of 27 tested children had a mutation in the protein tyrosine phosphatase, non-receptor-type 11 gene (PTPN11 gene).Interventions: GH was administered subcutaneously at 0.05 mg/kg per day until growth velocity was 1 cm/6 months.Main outcome measure: Linear growth (height) was measured at 3-month intervals in the first year and at 6-month intervals thereafter until final height.Results: At the start of treatment, median height SDS (H-SDS) was −2.8 (−4.1 to −1.8) and 0.0 (−1.4 to +1.2), based on national and Noonan standards respectively. GH therapy lasted for 3.0–10.3 years (median, 6.4), producing mean gains in H-SDS of +1.3 (+0.2 to +2.7) and +1.3 (−0.6 to +2.4), based on national and Noonan standards respectively. In 22 children with a mutation in PTPN11 mean gain in H-SDS for National standards was +1.3, not different from the mean gain in the five children without a mutation in PTPN11+1.3 (P=0.98).Conclusion: Long-term GH treatment in NS leads to attainment of adult height within the normal range in most patients.