This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.

Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome.

Pseudohypoparathyroidism type 1A (PHP1A), pseudoPHP (PPHP), and PHP type 1B (PHP1B) are caused by maternal and paternal GNAS mutations, and abnormal methylation at maternal GNAS promoter(s), respectively. Adult PHP1A patients are reportedly obese and short, whereas most PPHP patients are born small. In addition to PTH resistance, PHP1A and PHP1B patients may display early-onset obesity. As early-onset and severe obesity and short stature are daily burdens for PHP1A patients, we aimed at improving knowledge on the contribution of the GNAS transcripts to fetal and postnatal growth and fat storage. Through an international collaboration, we collected growth and weight data from birth until adulthood for 306 PHP1A/PPHP and 220 PHP1B patients. PHP1A/PPHP patients were smaller at birth than healthy controls, especially PPHP (length z-score PHP1A: −1.1±1.8; PPHP: −3.0±1.5). Short stature is observed in 64% and 59% of adult PHP1A and PPHP patients. PHP1B patients displayed early post-natal overgrowth (height z-score at 1 year: 2.2±1.3 and 1.3±1.5 in autosomal dominant and sporadic PHP1B) followed by a gradual decrease in growth velocity resulting in normal adult height (z-score for both: −0.4±1.1). Early-onset obesity characterizes GNAS alterations and is associated to significant overweight and obesity in adults (BMI z-score: 1.4±2.6, 2.1±2.0, and 1.4±1.9 in PPHP, PHP1A, and PHP1B, respectively), indicating that reduced Gsα expression is a contributing factor.. The growth impairment in PHP1A/PPHP may be due to Gsα haploinsufficiency in the growth plates; the paternal XLαs transcript likely contributes to prenatal growth; for all disease variants, a reduced pubertal growth spurt may be due to accelerated growth plate closure. Consequently, early diagnosis and close follow-up is needed in patients with GNAS defects to screen and intervene in case of early-onset obesity and decreased growth velocity.

CYP24A1 mutations are now accepted as a cause of idiopathic infantile hypercalcemia (IIH). A rapid liquid-chromatography tandem mass spectrometry (LC-MS/MS)-based blood test enabling measurement of the 25-OH-D :24,25-(OH) D ratio (R) can identify IIH patients on the basis of reduced C24-hydroxylation of 25-OH-D by CYP24A1 in vivo. Although values of this ratio are significantly elevated in IIH, somewhat surprisingly, serum 24,25-(OH) D remains detectable. The current study explores possible explanations for this including: residual CYP24A1 enzyme activity in individuals with certain CYP24A1 genotypes, expression of alternative C24-hydroxylases, and the possibility of isobaric contamination of the 24,25-(OH) D peak on LC-MS/MS. We employed an extended 20-min run time on LC-MS/MS to study serum vitamin D metabolites in patients with IIH due to mutations of CYP24A1 or SLC34A1; in unaffected heterozygotes and dialysis patients; in patients with vitamin D deficiency; as well as in normal subjects exhibiting a broad range of 25-OH-D levels. We identified 25,26-(OH) D as a contaminant of the 24,25-(OH) D peak. In normals, the concentration of 24,25-(OH) D greatly exceeds 25,26-(OH) D ; however, 25,26-(OH) D becomes more significant in IIH with CYP24A1 mutations and in dialysis patients, where 24,25-(OH) D levels are low when CYP24A1 function is compromised. Mean R in 30 IIH-CYP24A1 patients was 700 (range, 166 to 2168; cutoff = 140) as compared with 31 in 163 controls. Furthermore, patients possessing CYP24A1 L409S alleles exhibited higher 24,25-(OH) D levels and lower R (mean R = 268; n = 8) than patients with other mutations. We conclude that a chromatographic approach which resolves 24,25-(OH) D from 25,26-(OH) D produces a more accurate R that can be used to differentiate pathological states where CYP24A1 activity is altered. The origin of the residual serum 24,25-(OH) D in IIH patients appears to be multifactorial. © 2017 American Society for Bone and Mineral Research.