RASopathies are a heterogeneous group of conditions of the RAS/mitogen-activated protein kinase pathway presenting with overlapping features such as growth deficiency, neurodevelopmental disorders, cardiac defects, craniofacial dysmorphisms, cutaneous and ocular abnormalities, and increased cancer risk. This retrospective study analyzed the medical records regarding clinical and molecular data from 2018 to 2024 in a single center for rare diseases of individuals diagnosed with Noonan syndrome and related disorders previously submitted to diagnostic molecular analysis through next-generation sequencing techniques. Twenty-four patients were enrolled with an even sex ratio distribution and ages ranging from 1 month to 16 years at first evaluation. The main reason for referral was diagnostic assessment due to a combination of dysmorphic features (24/24; 100%), growth deficiency (18/24; 75%), neurodevelopmental disorders (15/24; 62.5%), and/or heart disease (13/24; 54.1%). Final diagnoses included 15 individuals with Noonan syndrome (nine with variants in PTPN11, two in SOS1, and one each in LZTR1, A2ML1, and MRAS, besides one with variants in both LZTR1 and SOS1), two with Noonan syndrome with multiple lentigines (both with variants in PTPN11), two with Neurofibromatosis-Noonan (NF1), two with cardiofaciocutaneous syndrome (BRAF), and one each with Noonan syndrome-like with loose anagen hair (PPP1CB), Noonan syndrome-like (CBL), and Costello syndrome (HRAS); one individual presented with a double diagnosis of Noonan and Klinefelter syndromes. Three pairs of unrelated patients presented recurrent variants in the PTPN11 gene, partially concordant in phenotypic correlation among the pairs but not fully concordant compared to previously described cases in the literature. Undescribed features in this group included myopathy and megacolon in a patient with Noonan syndrome-like, hypogonadotropic hypogonadism, and azoospermia in a patient with Noonan syndrome-like with loose anagen hair, and schizophrenia in a patient with Costello syndrome. One patient with Noonan syndrome had a novel variant of the A2ML1 gene (c.1829G>A), but the variant was strictly of uncertain significance, while c.2033G>A in the LZTR1 gene and c.1A>G in the NF1 gene are variants for the first time associated with features of Noonan syndrome.

Mutations in the SOX2 gene have been previously linked to a syndromic form of isolated hypogonadotropic hypogonadism, with additional ocular and neurodevelopmental phenotypes. Recently, we reported a functional role for SOX2 in hypothalamic kisspeptin-expressing neurons and established a mechanistic relationship between SOX2 heterozygous variants and isolated hypogonadotropic hypogonadism. To further test the role of Sox2 in the hypothalamic-pituitary-gonadal axis, we generated mice with a whole-body heterozygous knockout of Sox2 (Sox2WT/KO). We found that heterozygous loss of Sox2 significantly delayed pubertal onset in both male and female Sox2WT/KO mice compared to wild-ype (WT) controls. In females, fertility was also compromised, with fewer estrous cycles and a significant delay in time to first litter of Sox2WT/KO dams compared to WT controls. Circulating levels of gonadotropins were normal in both male and female Sox2WT/KO mice, suggesting a functional pituitary. Finally, we assessed the number of kisspeptin and GnRH neurons and found that Sox2WT/KO mice do not differ from controls in the number of kisspeptin neurons but have significantly fewer GnRH neurons. This deficit occurs before birth, as by embryonic day 15.5, there are already fewer GnRH neurons in the Sox2WT/KO mice. Using luciferase assays, we determined that Sox2 increases expression of GnRH in vitro; thus, the decrease in GnRH-expressing neurons in vivo is likely the result of Sox2 haploinsufficiency. Together, these data further substantiate a critical role for SOX2 in the hypothalamic-pituitary-gonadal axis via effects on GnRH neuron development and, therefore, pubertal timing and reproductive function.

CHARGE syndrome (CS), a rare and complex autosomal dominant disorder characterized by ocular coloboma, cardiac defects, choanal atresia, growth retardation, genital abnormalities, and ear malformations, is caused primarily by variants in the chromodomain helicase DNA-binding protein 7 (CHD7) gene. The clinical manifestations of CS frequently overlap with those of idiopathic hypogonadotropic hypogonadism (IHH), complicating diagnosis and management. To date, only a few cases of preterm infants with CS have been reported. Here, we describe the clinical features and genetic findings of a very preterm male infant who was initially diagnosed with IHH but was ultimately confirmed to have CS, carrying a de novo heterozygous CHD7 variant, highlighting the diagnostic and management challenges associated with this condition. A preterm male infant, born at 28 + 2 weeks with a birth weight of 1.15 kg, presented with micropenis and right radial polydactyly. Initial suspicion of IHH arose due to micropenis, cryptorchidism, and low levels of testosterone, LH, and FSH. Despite normal cranial MRI findings, further investigations revealed hsPDA, aortic arch narrowing, renal pelvis separation, and EEG abnormalities. Comprehensive genetic analyses, including whole-exome sequencing (WES), Sanger sequencing, and a Mini-gene Assay, confirmed the presence of a pathogenic de novo splicing variant in the CHD7 gene [c.5405-7G > A (NM_017780.4)]. As dysmorphic features progressed, the diagnosis was revised from IHH to CHARGE syndrome. Despite surgical and supportive treatments, the infant developed CRE sepsis and passed away after the withdrawal of life support. To our knowledge, this is the first reported case of CS with polydactyly in a very preterm infant at approximately 28 weeks gestation. Furthermore, we summarized the clinical and genetic findings of previously reported cases with overlapping CS and IHH phenotypes. This study expands the clinical phenotypes of CHD7-related disorders and provides new insights into early diagnosis, management, and future research on the relationship between CS and IHH.

Background The Bardet-Biedl syndrome (BBS) is a rare multisystem ciliopathy characterized by retinal degeneration, polydactyly, truncal obesity, hypogonadism, and hypogonadotropism. Progressive rod-cone dystrophy leads to early-onset vision loss. Despite increased genetic screening, BBS remains underdiagnosed in Caribbean populations. This study aims to describe the genetic and ocular phenotype of patients with BBS in Puerto Rico and explore genotype-phenotype correlations. Methods We conducted a retrospective chart review of 36 genetically confirmed BBS patients from a hereditary retinal disease clinic in Puerto Rico. Data collected included best-corrected visual acuity (BCVA), refractive error, visual field mean deviation (MD), and macular optical coherence tomography (OCT) measurements (volume and thickness). Genetic testing identified the BBS subtype and zygosity. Descriptive and statistical analyses were performed. The study was approved by a certified institutional review board (IRB).  Results Age ranged from three to 69 years old. Mutations in the BBS1 gene were most frequent (86%), followed by BBS7 (8%), BBS10 (3%), and BBS19 (3%). Most patients had homozygous mutations in the BBS1 (%). The mean BCVA was 2.0 logMAR OD and 2.1 logMAR OS. Patients with homozygotic mutations in the BBS1 had worse vision than compound heterozygotes (p=0.025). Upon visual field examination, the MD was -27.6 dB OD and -28.3 dB OS. Near-absent visual fields occurred in patients with advanced disease. Macular volume and thickness averaged 8.2 mm³/227 µm (OD) and 7.7 mm³/216 µm (OS). Structural damage was associated with inner/outer segment disruption on OCT. Conclusions Mutations in the BBS1 are the most frequent in Puerto Rico, often associated with profound visual impairment and retinal thinning. These findings underscore the importance of early ophthalmic evaluation and genetic testing in patients with syndromic retinitis pigmentosa. Genotype-specific differences in visual decline support personalized surveillance and future therapeutic planning.

49,XXXXY is a rare sex chromosome aneuploidy with an estimated incidence of 1 in 85,000-100,000 newborn males. Individuals with this syndrome exhibit variable clinical manifestations, typically including developmental delay, intellectual deficits, hypogonadism, and distinctive facial features such as ocular hypertelorism, epicanthic folds, a flat nasal bridge, prognathism, folded-over ears, and a short neck. Unlike patients with Klinefelter syndrome, they are often short in stature. Cornelia de Lange syndrome (CdLS) is an unrelated rare disorder with an incidence of 1 in 10,000-30,000 live births, affecting both sexes. CdLS shares overlapping features with 49,XXXXY, including intellectual deficits and hypogonadism. However, it also presents with unique facial characteristics, such as synophrys, thick or highly arched eyebrows, low-set ears, upturned nasal tips, long eyelashes, and microcephaly. CdLS is a clinically and genetically heterogeneous condition, with severe cases involving congenital malformations including limb anomalies, and milder cases showing only subtle facial dysmorphism. Both syndromes may also involve cardiac and renal anomalies. We report the first documented concurrence of 49,XXXXY and X-linked CdLS, emphasizing the challenges in diagnosis and the phenotypic overlap between these two rare syndromes, and propose a theoretical mechanism for the co-occurrence.