3ß-Hydroxysteroid Dehydrogenase Type 2 (3ßHSD2) Deficiency due to a Novel Compound Heterozygosity of a Missense Mutation (p.Thr259Met) and Frameshift Deletion (p.Lys273ArgFs*7) in an Undervirilized Infant Male with Salt Wasting.

Deficiency of 3ß-hydroxysteroid dehydrogenase type 2 (3ßHSD2) is a rare type of congenital adrenal hyperplasia (CAH), causing impaired steroid hormone production in both adrenals and gonads. Phenotype ranges, according to the genetic defect, from the salt-wasting form in both sexes to undervirilization in males and virilization in females. We present a 13-month-old male infant who was admitted to the hospital with signs of adrenocortical insufficiency and genital ambiguity. Clinical presentation, hormonal profile, laboratory evaluation, and karyotype were suggestive of the salt-wasting form of CAH due to 3ßHSD2 deficiency. Mutational analysis revealed a missense mutation c.776C>T (p.Thr259Met), inherited by the mother, and a frameshift deletion c.818-819delAA (p.Lys273ArgFs*7), inherited by the father. Both mutations are considered pathogenic. To our knowledge this is the first case of an undervirilized male infant with salt wasting bearing this pathogenic frameshift deletion p.Lys273ArgFs*7 in compound heterozygosity with the missense mutation p.Thr259Met.

Growth Hormone Deficiency due to p.(Gln467Argfs*64) Mutation in the ARID1B Gene in a Girl with Coffin-Siris Syndrome.

Introduction: Coffin-Siris syndrome (CSS) (MIM #135900) is an extremely rare genetic multisystemic disorder characterized by aplasia or hypoplasia of the upper phalanx of the fifth finger, moderate to severe cognitive and/or developmental delay, and characteristic facial features (thick lashes, hypertrichosis of the trunk, sparse hair). Congenital anomalies of the brain, kidney, and heart have been described but are less consistent across patients. Case presentation: We report a case of a 12-year-5-month-old girl with the clinical features of CSS, severe scoliosis, and epilepsy. Growth hormone deficiency was diagnosed at the age of 9 years. Recombinant human growth hormone (rhGH) treatment was started that resulted in a significant improvement of the growth velocity up to 5.4 cm/year (>90-97th centile). Next-generation sequencing identified a mutation in the ARID1B gene. Discusion: Despite its phenotypic heterogeneity, key features of CSS have become clearer and along with molecular diagnosis, a further global approach to improve the care of these individuals is enabled. Appropriate therapies for this population are needed to optimize growth and intellectual potentials.

Novel Hemizygous Missense Variant of Spermine Synthase (SMS) Gene Causes Snyder-Robinson Syndrome in a Four-Year-Old Boy.

Snyder-Robinson syndrome (SRS) is an extremely rare X-linked intellectual disability syndrome (MRXSSR; MIM #309583). The main clinical features of SRS include psychomotor delay, hypotonia, and asthenic-type body habitus - reduced body weight and bone abnormalities (osteoporosis, fractures, kyphoscoliosis). We report a case of SRS with a hemizygous missense variant in the SMS gene,c.334C>G (p.Pro112Ala), in a 4-year-old boy, who initially developed hypotonia, delayed motor skills, and subsequently epilepsy. This variant in SMS was found to be de novo. To the best of our knowledge, this novel SMS gene variant has never been previously reported in disease-related variation databases, such as ClinVar or HGMD.

17p13.1 Microduplication Syndrome in a Child, Familial Short Stature, and Growth Hormone Deficiency: A Case Report and Review of the Literature.

To date, 6 cases of 17p13.1 microduplications have been described in the literature. Intellectual disability is the core feature, together with minor facial dysmorphisms and obesity. We describe the first case of a young patient with a maternally inherited microduplication in 17p13.1 presenting with growth hormone deficiency. The boy was addressed to the endocrine division for growth retardation (weight and height <3rd percentile). Besides minor facial dysmorphisms, physical and neurological examinations were normal except for motor dyspraxia. Basic blood tests and endocrinological investigations were normal, but IGF1 levels were low for his age. Growth hormone deficiency was confirmed. Hypothalamic pituitary MRI was normal. His karyotype was 46XY. Array-CGH analysis detected a 422-kb copy number gain in the spanning region 17p13.1 inherited from his mother. Although familial short stature is considered a "normal" variation of growth retardation, hormonal and genetic investigation is essential in the etiological diagnosis.

The mystery of puberty initiation: genetics and epigenetics of idiopathic central precocious puberty (ICPP).

Puberty is a major developmental stage. Damaging mutations, considered as "mistakes of nature", have contributed to the unraveling of the networks implicated in the normal initiation of puberty. Genes involved in the abnormal hypothalamic-pituitary-gonadal (HPG) axis development, in the normosmic idiopathic hypogonadotropic hypogonadism (nIHH), in the X-linked or autosomal forms of Kallmann syndrome and in precocious puberty have been identified (GNRH1, GNRHR, KISS1, GPR54, FGFR1, FGF8, PROK2, PROKR2, TAC3, TACR3, KAL1, PROK2, PROKR2, CHD7, LEP, LEPR, PC1, DAX1, SF-1, HESX-1, LHX3, PROP-1). Most of them were found to play critical roles in HPG axis development and regulation, the embryonic GnRH neuronal migration and secretion, the regulation and action of the hypothalamic GnRH. However, the specific neural and molecular mechanisms triggering GnRH secretion remain one of the scientific enigmas. Although GnRH neurons are probably capable of autonomously generating oscillations, many gonadal steroid-dependent and -independent mechanisms have also been proposed. It is now well proven that the secretion of GnRH is regulated by kisspeptin as well as by permissive or opposing signals mediated by neurokinin B and dynorphin. These three supra-GnRH regulators compose the kisspeptin-neurokinin B-dynorphin neuronal (KNDy) system, a key player in pubertal onset and progression. Moreover, an ongoing increasing number of inhibitory, stimulatory and permissive networks acting upstream on GnRH neurons, such as GABA, NPY, LIN28B, MKRN3 and others integrate diverse hormonal and peripheral signals and have been proposed as the "gate-keepers" of puberty, while epigenetic modifications play also an important role in puberty initiation.

Absence of GPR54 and TACR3 mutations in sporadic cases of idiopathic central precocious puberty.

BACKGROUND/AIMS: Kisspeptin (KISS1)/GPR54 (KISSR) signaling complex and neurokinin B (NKB)/NKB receptor (TACR3) signaling have been proposed as an integral part of the network coordinating GnRH release. GPR54 (KISS1R) and TACR3 gene mutations have been described in cases of idiopathic hypogonadotrophic hypogonadism, while limited data exist on gain-of-function mutation in GPR54 (KISS1R) gene causing idiopathic central precocious puberty (ICPP). No data on TACR3 mutations in ICPP have been described so far. The aim of this study was to elucidate the possible impact of GPR54 (KISS1R) and TACR3 mutations in ICPP. METHODS: PCR-amplified genomic DNA of 38 girls with ICPP was analyzed for GPR54 and TACR3 gene mutations. RESULTS: No GPR54 or TACR3 mutations were found. The A/G coding sequence single nucleotide polymorphism (SNP) on the GPR54 gene (dbSNP ID: rs10407968) was found in 2 patients with ICPP. CONCLUSION: Our data indicate that GPR54 and TACR3 gene mutations are not a frequent cause of ICPP. The identified A/G synonymous SNP (dbSNP ID: rs10407968) located in exon 1 of the gene is not likely to have a pathogenic role in exon splicing and therefore in the premature initiation of puberty.