Waardenburg syndrome (WS) is a complex genetic disorder primarily characterized by auditory and pigmentary abnormalities, resulting from neural crest cell migration disorders. We reported 2 genetically confirmed SOX10-mutant WS cases illustrating critical management principles. Both patients underwent early auditory intervention (case 1: cochlear implantation at age 3; case 2: hearing aids from age 2), resulting in preserved age-appropriate language acquisition. Each case manifested delayed puberty with biochemical evidence of hypogonadotropic hypogonadism, necessitating gonadotropin therapy to potentiate virilization and preserve fertility. Multidisciplinary care and emerging therapeutic approaches offer hope for better management. Further studies are warranted to improve the diagnosis, treatment, and quality of life of patients with WS. USP7-related Hao-Fountain syndrome is characterized by developmental delay in 100% of individuals, although intellectual disability is variable, with up to 50% of affected individuals having intellect in the normal range. Muscular hypotonia is also common; this tends to improve over time, but some affected individuals develop hypertonia. About two thirds of affected individuals have an abnormal/unsteady gait and about one quarter have contractures, most commonly involving large joints and joints of the lower extremities. Neuropsychiatric features can include autism, attention-deficit/hyperactivity disorder (ADHD), and behavioral issues such as stubbornness and compulsivity. Feeding difficulties are common and can require special feeding techniques, including use of a feeding tube. Gastroesophageal reflux disease, dysphagia, and hyperphagia have also been reported. Eye and vision issues (hyperopia, strabismus, nystagmus) are seen in more than 50% of affected individuals. About half of affected individuals have impaired bone mineralization, which can lead to fractures. Findings in fewer than 50% of individuals include epilepsy, sleep disturbance, hypogonadism, scoliosis, and hearing loss. The diagnosis of USP7-related Hao-Fountain syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in USP7 identified by molecular genetic testing. Treatment of manifestations: Feeding therapy for poor weight gain / dysphagia; gastrostomy tube placement may be required for persistent feeding issues; consultation with a dietician when hyperphagia and/or obesity is present; adequate intake of Ca2+ and vitamin D for reduced bone mineral density. Standard treatment for developmental delay / intellectual disability, epilepsy, gastroesophageal reflux disease, diarrhea, constipation, eye issues, sleep disturbance, cryptorchidism, micropenis, hypothyroidism, growth hormone deficiency, adrenal insufficiency, and hearing loss. Surveillance: At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake; monitor for signs/symptoms of constipation and gastroesophageal reflux disease; monitor those with seizures; assess for new manifestations such as seizures, changes in tone, and gait abnormalities; monitor developmental progress and educational needs; monitor for scoliosis, contractures, mobility, and self-help skills; monitor for evidence of aspiration, respiratory insufficiency, and sleep disturbance (including for signs/symptoms of sleep apnea); monitor for signs and symptoms of puberty starting at about age seven years to the late teenage years. Annually, behavioral assessment for anxiety, ADHD, autism spectrum disorder, aggression, and self-injury; evaluate for hypothyroidism; audiology evaluation (in childhood). Assess bone mineral density every two years starting at age five years and then every three to five years in adulthood. Ophthalmology evaluation and endocrinologic tests for adrenal insufficiency as clinically indicated. USP7-related Hao-Fountain syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with USP7-related Hao-Fountain syndrome inherited a pathogenic variant from a parent. Each child of an individual with USP7-related Hao-Fountain syndrome has a 50% chance of inheriting the pathogenic variant. Once the USP7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

H syndrome, a rare autosomal recessive disorder, is caused by pathogenic variants in the SLC29A3 gene located on chromosome 10q22. The clinical phenotype encompasses diverse manifestations, including hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, short stature, hyperglycemia with insulin-dependent diabetes mellitus, and hallux valgus/flexion contractures. A 20-year-old Syrian male born to consanguineous parents presented with fever, productive cough, chest pain, dyspnea, and scrotal discomfort. His medical history included progressive bilateral sensorineural hearing loss, failure to thrive, and significant short stature (height 1.46 m and weight 44 kg). Physical examination revealed conjunctival pallor, icterus, jugular vein distention, hypertrichosis, hypoplastic genitalia, and decreased breath sounds and dullness to percussion that were consistent with pneumonia and pleural effusion. Hormonal evaluation indicated primary hypogonadism and growth hormone deficiency. Echocardiography revealed pulmonary hypertension and tricuspid valve insufficiency. Chest imaging confirmed bilateral pleural effusion and lung infiltrates. The constellation of clinical findings, including hypogonadism, hypertrichosis, hallux valgus, and hepatosplenomegaly, collectively suggested H syndrome. The patient received supplemental oxygen therapy, resulting in improved oxygen saturation. Empirical antibiotic therapy consisting of intravenous ceftriaxone and levofloxacin was administered for 10 days, resulting in clinical improvement and resolution of respiratory symptoms. Given the high prevalence of this condition among consanguineous populations within resource-limited settings, this report emphasizes the critical need for accessible genetic testing and heightened clinical awareness of this rare disorder.

The phenotypic similarities and genetic heterogeneity occurring in diverse forms of Ehlers Danlos Syndrome (EDS) subtypes and many heritable connective tissue disorders can pose a diagnostic challenge. In the wake of the growing applications of next-generation sequencing technologies including exome and genome sequencing, opportunities for achieving definitive genetic diagnosis are increasingly arising. We present a 46-year-old man with joint laxity, recurrent joint subluxations, pelvic floor dysfunction, and postural orthostatic tachycardia syndrome (POTS), who was referred for EDS assessment. His medical history included morbid obesity requiring gastric bypass surgery, hearing loss, asthma, retinopathy, myopia, atrial septal defect, narcolepsy with cataplexy, polyneuropathy, folliculitis, lichen simplex chronicus, atopic dermatitis, and hypogonadism. His family history was significant for multiple first- and second-degree relatives who died from cardiac diseases including cases of childhood deaths. Physical examination showed joint laxity with Beighton score of 3/9, bilateral pes planus, hearing loss and macrocephaly. Exome sequencing revealed heterozygous variants LMNA c.1262 T > C p.L421P [classified as likely pathogenic], FLG c.2282_2285del p. S761Cfs*36 [classified as pathogenic], and FLG c.1501 C > T p. R501* [classified as pathogenic]. Mitochondria sequencing revealed a variant of uncertain significance (VUS), MT-ND2 m.5047 T > C p.V193A that is present at 9% heteroplasmy in blood. These findings show co-occurrence of pathogenic sequence variants in neighboring genes located in chromosome 1q2 region [LMNA and FLG] in a patient with features of hereditary connective tissue disorders. Our study highlights the capability of exome sequencing in achieving some actionable diagnosis in cases of co-morbid genetic disorders with overlapping and non-specific symptoms.

Adolescents and young adults (AYA) with rare forms of diabetes - including Wolfram syndrome (WS), Alström syndrome (AS), Bardet-Biedl syndrome (BBS), and maturity-onset diabetes of the young (MODY) - face unique challenges during the transition to adult care. These challenges are intensified by multisystem endocrine involvement, neurocognitive and sensory impairments, and limited adult provider expertise. This narrative review describes transition-specific barriers in rare diabetes syndromes, explores current initiatives, and proposes recommendations for care models and health system reform. Syndromic forms of diabetes often involve complex endocrine dysfunctions beyond glycemic control, including diabetes insipidus, hypogonadism, and thyroid or pituitary anomalies. Transitions are further hindered by diagnostic uncertainty, fragmented care structures, and insufficient interdisciplinary coordination. Pediatric care is often proactive and family-centered, while adult services are fragmented and reactive. Dedicated multidisciplinary transition services remain scarce. Best practices include early transition planning, syndrome-specific education, the use of patient-reported outcome measures (PROMs), and integration of digital tools. Structured collaboration between pediatric and adult providers - including virtual models - should be supported. Patient-centered approaches must address both medical and psychosocial readiness, with tailored communication for those with sensory or cognitive impairments. Sustainable transition programs require dedicated funding, institutional prioritization, and policy inclusion in national and European rare disease frameworks. Without adequate financial support, disparities in care continuity and outcomes are likely to persist. A coordinated, multidisciplinary, and resourced transition model is essential to safeguard health, autonomy, and long-term outcomes in AYA with rare diabetes syndromes. Young people with rare forms of diabetes - such as Wolfram syndrome (WS), Alström syndrome (AS), Bardet-Biedl syndrome (BBS), or maturity-onset diabetes of the young (MODY) - face special challenges when moving from pediatric to adult healthcare. These rare conditions often affect more than just blood sugar and can involve vision, hearing, and other parts of the body. As they grow older, these adolescents must not only manage their complex health needs but also learn to take more responsibility for their care. This article explains why the transition to adult care is especially difficult for this group. It shares experiences from families and healthcare providers and describes what can help: early preparation, teamwork between child and adult doctors, digital tools, and emotional support. The authors call for stronger guidelines and better cooperation across healthcare systems so that young people with rare diabetes can stay healthy and feel supported during this important time in life.

Background: Wolfram syndrome (WFS), also known as DIDMOAD, is a rare monogenic neurodegenerative disorder characterized by four key components: non-autoimmune insulin-dependent diabetes mellitus (DM), optic atrophy, sensorineural hearing loss, and diabetes insipidus. Although it significantly affects quality of life, gonadal dysfunction, particularly hypogonadism, remains underrecognized. Methods: In total, 45 patients (25 men, 20 women) with genetically confirmed WFS from a single tertiary-care center were prospectively followed to assess gonadal function. Men underwent hormonal evaluations, semen analysis, imaging tests, and testicular biopsies. In women, data on age at menarche, menstrual irregularities, and age at menopause were recorded. Hormonal analyses, including anti-Müllerian hormone (AMH) levels, and imaging tests were also conducted. Results: Hypogonadism was identified in 19 men (76.0%), of whom 17 (68.0%) had hypergonadotropic hypogonadism and 2 (8.0%) had hypogonadotropic hypogonadism. Testicular biopsies showed seminiferous tubule damage, Sertoli cell predominance, and reduced Leydig cells. Azoospermia was observed in 12 patients, whereas others presented with oligozoospermia, teratozoospermia, or asthenozoospermia. Most patients exhibited low testosterone levels along with elevated LH and FSH, suggesting primary testicular failure, except for two cases of hypogonadotropic hypogonadism. Correlations between biomarkers, onset age and severity have been analyzed and provide important insights regarding medical treatment. In women, menstrual irregularities were universal, with 20% experiencing premature menopause. Four patients had low AMH levels, with ovarian atrophy in three and a postmenopausal uterus in two, indicating early hypogonadism risk. Conclusions: Gonadal dysfunction is a significant yet overlooked feature of WFS, requiring systematic evaluation during puberty and beyond. Proper management is essential to mitigate metabolic disturbances and psychological impacts, including infertility distress, relationship challenges, and quality of life concerns. Addressing sexual health is crucial as WFS patients live longer and aspire to establish relationships or start families.