Adult height improved over decades in patients with X-linked hypophosphatemia: a cohort study.

OBJECTIVES: The aim of this study is to analyze height after cessation of growth (final height [FH]) and its evolution over the last decades in X-linked hypophosphatemia (XLH) patients in France, as the data on natural history of FH in XLH are lacking. DESIGN: We performed a retrospective observational study in a large cohort of French XLH patients with available data on FH measurements. MATERIALS AND METHODS: We divided patients into 3 groups according to their birth year: group 1 born between 1950 and 1974, group 2 born between 1975 and 2000, and group 3 born between 2001 and 2006, respectively, and compared their FHs. RESULTS: A total of 398 patients were included. Mean FHs were the following: for group 1, -2.31 ± 1.11 standard deviation score (SDS) (n = 127), 156.3 ± 9.7 cm in men and 148.6 ± 6.5 cm in women; for group 2, -1.63 ± 1.13 SDS (n = 193), 161.6 ± 8.5 cm in men and 153.1 ± 7.2 cm in women; and for group 3, -1.34 ± 0.87 SDS (n = 78), 165.1 ± 5.5 cm in men and 154.7 ± 6 cm in women. We report a significant increase in mean FH SDS over 3 generations of patients, for both men and women (P < .001). Final height SDS in male (-2.08 ± 1.18) was lower than in female (-1.70 ± 1.12) (P = .002). CONCLUSION: The FH of XLH patients in France increased significantly over the last decades. Even though men's FHs improved more than women's, men with XLH remain shorter reflecting a more severe disease phenotype. While the results are promising, most patients with XLH remain short leaving room for improvement.

Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease.

INTRODUCTION: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare genetic disease associated with loss-of-function variations in the gene encoding the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1). Phenotype-genotype correlation is unclear. Long-term outcome data are lacking. The objective of this study was to describe characteristics and outcomes to search for a phenotype-genotype correlation. METHODS: We retrospectively collected clinical data, genetic features, and outcomes from 24 genetically confirmed cases from 10 French centers; results are presented as median (min-max). RESULTS: Clinical symptoms at diagnosis (age, 1.5 [0.5-8.7] years) were mainly bone and neurological abnormalities, and laboratory data showed hypocalcemia (1.97 [1.40-2.40] mmol/L), hypophosphatemia (-3.4 [-13.4 to (-)0.2] SD score for age), low 25OHD and low 1,25(OH)2D3, secondary hyperparathyroidism with PTH at 6.6 (1.3-13.7) times the upper limit for normal (ULN; PTH expressed as ULN to homogenize data presentation), and increased alkaline phosphatase (1968 [521-7000] IU/L). Bone radiographs were abnormal in 83% of patients. We identified 17 variations (11 missense, 3 frameshift, 2 truncating, and 1 acceptor splice site variations) in 19 families (homozygous state in 58% [11/19]). The partial loss-of-function variation p.(Ala129Thr) was associated with a milder phenotype: older age at diagnosis, higher serum calcium (2.26 vs 1.85 mmol/L), lower PTH (4.7 vs 7.5 ULN), and lower alkaline phosphatase (759 vs 2082 IU/L). Patients were treated with alfacalcidol. Clinical (skeletal, neurological), biochemical, and radiological outcomes were satisfactory, and complications occurred if there was bad adherence. CONCLUSION: Overall, our findings highlight good outcomes under substitutive treatment and the need of a closer follow-up of eyes, teeth, kidneys, and blood pressure in VDDR1A.

Growth hormone treatment improves final height in children with X-linked hypophosphatemia.

BACKGROUND/AIM: Despite optimal conventional treatment (oral phosphate supplements and active vitamin D analogs), about 40-50% of children with well-controlled X-linked hypophosphatemia (XLH) show linear growth failure, making them less likely to achieve an acceptable final height. Here, we studied the hypothesis that rhGH treatment improves final height in children with XLH and growth failure. METHODS: Two cohorts of children with XLH were included in this retrospective longitudinal analysis: (1) a cohort treated with rhGH for short stature (n = 34) and (2) a cohort not treated with rhGH (n = 29). The mean duration of rhGH treatment was 4.4 ± 2.9 years. We collected the auxological parameters at various time points during follow-up until final height. RESULTS: In rhGH-treated children, 2 years of rhGH therapy was associated with a significant increase in height from - 2.4 ± 0.9 to - 1.5 ± 0.7 SDS (p < 0.001). Their mean height at rhGH discontinuation was - 1.2 ± 0.9 SDS and at final height was - 1.3 ± 0.9 SDS corresponding to 165.5 ± 6.4 cm in boys and 155.5 ± 6.3 cm in girls. Notably, the two groups had similar final heights; i.e., the final height in children not treated with rhGH being - 1.2 ± 1.1 SDS (165.4 ± 6.8 cm in boys and 153.7 ± 7.8 cm in girls), p = 0.7. CONCLUSION: Treatment with rhGH permits to improve final height in children with XLH and growth failure, despite optimal conventional treatment. We propose therefore that rhGH therapy could be considered as an option for short stature in the context of XLH.

Presenting features and molecular genetics of primary hyperparathyroidism in the paediatric population.

AIM: To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population. METHODS: Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018. RESULTS: Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, 'CaSR group'; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, 'cell proliferation group'; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in 'cell proliferation group' patients compared to those in the 'CaSR group' (P = 0.001 and 0.028, respectively). CONCLUSION: Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.

Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.

PURPOSE: XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. METHODS: We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS. RESULTS: Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10-10). Five variants are de novo (P value = 1.5 × 10-5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. CONCLUSION: DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.

Dental and craniofacial features associated with GNAS loss of function mutations.

BACKGROUND: Pseudohypoparathyroidism (PHP, OMIM #103580) is a very rare disease (incidence 0.3-1/100,000). Heterozygous inactivating mutations involving the maternal GNAS exons 1-13 that encodes the alpha subunit of the stimulatory G protein (Gsα) cause inactivating parathyroid hormone (PTH)/PTHrP signalling disorder type 2 (iPPSD2 or PHP type 1A), which is characterized by Albright hereditary osteodystrophy and resistance to multiple hormones that act through the Gsα signalling pathway (including PTH, thyroid-stimulating hormone, and α-melanocyte-stimulating hormone). To date, little information is available on craniofacial features in patients with PHP. The small number of patients studied in previous reports as well as the lack of molecular characterization of the patients may have precluded the detection of specific orofacial manifestations in the different PHP subtypes. MATERIALS/METHODS: We conducted a systematic analysis of dental and craniofacial features in 19 patients with iPPSD2 and maternal GNAS inactivating mutations to assess the frequency and specificity of the anomalies. RESULTS: Facial examinations showed reduced vertical, sagittal, and transverse development of the mid-facial structures. Intraoral and radiographic examinations revealed that 89 per cent of the patients had at least one dental anomaly, including tooth submergence leading to severe infraocclusion in 83 per cent of cases. Craniofacial analysis of lateral cephalometric radiographs also showed a significant alteration in the development of the cranial base and maxillary and mandibular structures in these patients. CONCLUSIONS: Patients with iPPSD2 and maternal GNAS mutations had specific craniofacial alterations and dental abnormalities. These specific defects should be assessed in order to provide appropriate dental and orthodontic care to these patients. (clinical trial registration: 1920371 v 0, French Nationale Data Processing and Liberties Commission - CNIL).

Two-year recombinant human growth hormone (rhGH) treatment is more effective in pre-pubertal compared to pubertal short children with X-linked hypophosphatemic rickets (XLHR).

CONTEXT: Twenty-five to 40% of patients with well-controlled X-linked hypophosphatemic rickets (XLHR) have a final height under -2 SDS. Previous studies have shown that recombinant human growth hormone (rhGH) treatment improves linear growth in short children with XLHR. OBJECTIVE: We studied the effectiveness of rhGH treatment in children with XLHR in a larger cohort. DESIGN: Monocentric, prospective, non-randomized trial. SETTING: University hospital in France. PATIENTS: 19 patients with XLHR and a mutation in the PHEX gene. Six male and 6 female Tanner stage 1 patients (age 6.1±2.4years) and 4 male and 3 female Tanner stage 2 patients (age 13.1±1years). At inclusion, height SDS was -2.35±0.8 SDS and growth velocity was -1.12±1.2 SDS. INTERVENTION: 2years of treatment with 67mcg/kg/day of rhGH at initiation. Every three months rhGH dosage was adjusted using an IGF-1 dosing protocol. MAIN OUTCOME MEASURES: Comparison in change from baseline to year 2 in height and growth velocity. RESULTS: Height SDS improved from -2.35±0.8 SDS at baseline, to -1.62±0.8 SDS (p=0.01) after one and to -1.2±1 SDS (p=0.04) after two years of rhGH treatment. There was a strong correlation (r2=0.6104, p<0.0001) between the age of onset of rhGH treatment and the number of cm gained over the study period. Pre-pubertal patients height SDS improved compared to baseline height SDS after one (-1.5±0.7, p<0.03) and two (-0.96±1, p<0.03) years of rhGH treatment. In pubertal patients there was no significant improvement in height SDS after one year (-1.75±1) and after two years (-1.7±0.8) of rhGH treatment. CONCLUSION: Two-year rhGH treatment is effective to treat short stature in XLHR children. Pre-pubertal children responded better to rhGH. CLINICAL TRIAL REGISTRATION NUMBER: NCT02720770.

Association of environmental markers with childhood type 1 diabetes mellitus revealed by a long questionnaire on early life exposures and lifestyle in a case-control study.

BACKGROUND: The incidence of childhood type 1 diabetes (T1D) incidence is rising in many countries, supposedly because of changing environmental factors, which are yet largely unknown. The purpose of the study was to unravel environmental markers associated with T1D. METHODS: Cases were children with T1D from the French Isis-Diab cohort. Controls were schoolmates or friends of the patients. Parents were asked to fill a 845-item questionnaire investigating the child's environment before diagnosis. The analysis took into account the matching between cases and controls. A second analysis used propensity score methods. RESULTS: We found a negative association of several lifestyle variables, gastroenteritis episodes, dental hygiene, hazelnut cocoa spread consumption, wasp and bee stings with T1D, consumption of vegetables from a farm and death of a pet by old age. CONCLUSIONS: The found statistical association of new environmental markers with T1D calls for replication in other cohorts and investigation of new environmental areas. TRIAL REGISTRATION: Clinical-Trial.gov NCT02212522 . Registered August 6, 2014.

Severe sex differentiation disorder in a boy with a 3.8 Mb 10q25.3-q26.12 microdeletion encompassing EMX2.

The molecular basis of male disorders of sex development (DSD) remains unexplained in a large number of cases. EMX2 has been proposed to play a role in the masculinization process for the past two decades, but formal evidence for this causal role is scarce. The aim of this study is to yield additional support to this hypothesis by reporting on a male patient who presented with 46,XY DSD, a single kidney, intellectual disability, and the smallest microdeletion including EMX2 reported to date. EMX2 haploinsufficiency is likely to explain the masculinization defect observed in our patient, similar to what has been described in the mouse. In the case of cytogenetically diagnosed cases, deletions of EMX2 have been associated with a wide range of DSD, ranging from hypospadias to complete sex reversal.

Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus.

Krüppel-like transcription factors (KLFs) have elicited significant attention because of their regulation of essential biochemical pathways and, more recently, because of their fundamental role in the mechanisms of human diseases. Neonatal diabetes mellitus is a monogenic disorder with primary alterations in insulin secretion. We here describe a key biochemical mechanism that underlies neonatal diabetes mellitus insulin biosynthesis impairment, namely a homozygous mutation within the insulin gene (INS) promoter, c.-331C>G, which affects a novel KLF-binding site. The combination of careful expression profiling, electromobility shift assays, reporter experiments, and chromatin immunoprecipitation demonstrates that, among 16 different KLF proteins tested, KLF11 is the most reliable activator of this site. Congruently, the c.-331C>G INS mutation fails to bind KLF11, thus inhibiting activation by this transcription factor. Klf11(-/-) mice recapitulate the disruption in insulin production and blood levels observed in patients. Thus, these data demonstrate an important role for KLF11 in the regulation of INS transcription via the novel c.-331 KLF site. Lastly, our screening data raised the possibility that other members of the KLF family may also regulate this promoter under distinct, yet unidentified, cellular contexts. Collectively, this study underscores a key role for KLF proteins in biochemical mechanisms of human diseases, in particular, early infancy onset diabetes mellitus.

Disorders of sex development and Diamond-Blackfan anemia: is there an association?

Diamond-Blackfan anemia (DBA) is a rare disorder characterized by congenital pure red cell aplasia. Mutations in ribosomal protein S19 (RPS19) have been identified in 25% of DBA patients. More recently, mutations in other ribosomal protein genes, namely RPS7, RPS15, RPS24, RPS17, RPS27A, RPL35a, RPL36, RPL11, and RPL5, have also been found in patients with DBA. Approximately 30-40% of affected patients have various associated physical anomalies, mostly craniofacial and at the extremities, but also cardiac or urogenital malformations. Anomalies of the urogenital tract in DBA patients comprise changes in the kidney (dysplasia, agenesis, duplication, horseshoe kidney) and genitalia (hypospadias). To date, disorders of sex development (DSD) have only been described once in association with DBA. We report here four DBA patients who exhibited DSD.

Impaired sexual activity in male adults with partial androgen insensitivity.

CONTEXT: Choosing the sex of rearing of an XY neonate with a major sexual ambiguity and a mutated androgen receptor remains one of the more difficult questions of neonatal endocrinology. A direct consequence of this choice is the accomplishment of sexual function in adulthood. There is very limited knowledge of the sexual performance of patients with partial androgen insensitivity syndrome. OBJECTIVE: The objective of this study is to describe physical acts of sexuality in partial androgen insensitivity syndrome patients reared as males. DESIGN: We were able to obtain factual information regarding the sexual activity of 15 adult patients who had been reared as males and followed at our institution since birth. We evaluated their sexual performance using two validated questionnaires (Golombok-Rust Inventory of Sexual Satisfaction and International Index of Erectile Dysfunction). RESULTS: We documented a major impairment of all parameters of sexual activity. CONCLUSION: This long-term insight into the consequences of male sex assignment will have to be balanced by a study of the consequences of female sex assignment.