Mucopolysaccharidosis (MPS) represents a group of rare inherited metabolic disorders characterized by abnormal accumulation of glycosaminoglycans (GAGs) due to deficiencies of lysosomal enzymes. Mucopolysaccharidosis type I (MPS I) is caused by biallelic pathogenic variants in the IDUA gene and is inherited in an autosomal recessive pattern. The IDUA gene is located on chromosome 4p16.3 and encodes the lysosomal enzyme α-L-iduronidase, which plays a critical role in the degradation of GAGs, particularly dermatan sulfate and heparan sulfate. Reduced or absent IDUA enzymatic activity leads to the progressive accumulation of undegraded substrates within lysosomes, resulting in multisystem organ involvement. Based on clinical severity, MPS I is traditionally classified into three phenotypic subtypes: the severe form (Hurler syndrome), the intermediate form (Hurler-Scheie syndrome), and the attenuated form (Scheie syndrome, MPS I-S). This report describes a 13-year-old female patient in whom compound heterozygous pathogenic variants in the IDUA gene were identified by genetic testing, and whose clinical manifestations were consistent with the MPS I-S. In addition to typical skeletal and joint abnormalities, the patient also presented with uterine developmental abnormality. Currently, there is no definitive evidence supporting a direct causal relationship between MPS I and uterine developmental abnormalities; however, this case suggests a potential association between MPS I and reproductive system developmental abnormalities. This case may help further expand the phenotypic spectrum of MPS I and enhance clinical awareness of its multisystem involvement. PTDSS1-related Lenz-Majewski hyperostotic dysplasia (LMHD) is characterized by cutis laxa and progressive bone sclerosis, primarily affecting the skull and long bones. Individuals with classic PTDSS1-related LMHD typically presents in infancy with cutis laxa, prominent cutaneous veins, characteristic craniofacial features (disproportionately large head, broad forehead, delayed closure of the fontanelles, hypertelorism, large floppy ears, nasal obstruction / choanal atresia, macrostomia, thin vermilion of the lips, dental enamel hypoplasia, and prognathism or retrognathia), brachydactyly and syndactyly of the digits, early-onset osteosclerosis (involving the skull, spine, diaphyses of the long bones, clavicles, and ribs), severe growth deficiency, and significant developmental delays. Additional features can include genitourinary anomalies in males, inguinal hernia, ophthalmologic manifestations, hearing loss, and hydrocephalus. Attenuated PTDSS1-related LMHD is characterized by minimal or mild cutis laxa, slower progression of hyperostosis, preserved or mildly affected development, and normal stature. The diagnosis of PTDSS1-related LMHD is established in a proband with characteristic clinical and imaging findings and a heterozygous pathogenic gain-of-function variant in PTDSS1 identified by molecular genetic testing. Treatment of manifestations: Treatment of skeletal manifestations per orthopedist; consider physical therapy, occupational therapy, and assisted devices for mobility; decompression of cervical spine stenosis as needed; treatment of hydrocephalus as needed per neurosurgeon; treatment of respiratory difficulty and obstructive sleep apnea per otolaryngologist and/or pulmonologist; careful airway evaluation prior to surgical procedures; supportive therapies for those with developmental delays; individualized education plan for learning disorders and school performance issues; treatment of dental enamel hypoplasia per dentist; standard treatments for genitourinary anomalies, delayed puberty, inguinal hernia, vision issues, and hearing loss; consider dermatology referral for cosmetic concerns due to cutis laxa. Surveillance: Growth assessment and orthopedic evaluation annually or as determined by the orthopedist to monitor joint and skeletal manifestations; brain and spine MRI as needed; assess for manifestations of sleep apnea at each visit; polysomnography as needed; dental evaluation with frequency per dentist; ophthalmology evaluation with frequency per ophthalmologist; audiology evaluation as needed; monitor developmental progress, educational needs, and family needs at each visit. Agents/circumstances to avoid: Activities/procedures that involve extreme neck extension and flexion in individuals with craniovertebral junction stenosis. PTDSS1-related LMHD is an autosomal dominant disorder. All probands reported to date with PTDSS1-related LMHD whose parents have undergone molecular genetic testing have had the disorder as the result of a de novo PTDSS1 pathogenic variant. Risk to the parents of the proband of having another affected pregnancy is presumed to be low as the proband most likely has a de novo PTDSS1 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the possibility of parental gonadal mosaicism. Given this risk, prenatal and preimplantation genetic testing may be considered.

Coffin-Siris syndrome 12 (CSS12) is a recently described neurodevelopmental disorder caused by heterozygous pathogenic variants in BICRA, a gene encoding a core subunit of the non-canonical BAF (ncBAF) chromatin-remodeling complex. The condition is characterized by developmental delay, hypotonia, hypertrichosis, and joint laxity. However, long-term data remain limited, and systemic manifestations are incompletely defined. We report a 22-year-old male with a de novo BICRA frameshift variant, c.2479_2480delinsA (p.Ala827Thrfs*15), previously included in the original cohort reported by Barish et al. Longitudinal follow-up revealed an expanded phenotype extending beyond neurodevelopmental features. Early findings included global developmental delay, growth hormone deficiency, short stature, and joint hypermobility. In adolescence and adulthood, he developed severe intestinal dysmotility requiring total colectomy, recurrent spontaneous pneumothoraces from bilateral apical bullous disease, and portal-vein thrombosis, representing visceral and vascular complications not previously emphasized in BICRA-related disorders. The identified BICRA variant truncates the coiled-coil domain critical for BRD9/BRD4 interaction, consistent with a loss-of-function mechanism. The patient's systemic features suggest that BICRA haploinsufficiency affects not only neurodevelopmental pathways but also smooth-muscle and connective-tissue integrity. This case expands the phenotypic spectrum of BICRA-related CSS12, demonstrating that visceral and vascular involvement can occur alongside neurodevelopmental and connective-tissue features. Recognition of these broader manifestations underscores the need for lifelong multidisciplinary surveillance and contributes to understanding the diverse biological roles of the ncBAF complex in human development.

Haploinsufficiency of KDM3B has also been linked to developmental delay, intellectual disability, autism spectrum disorder (ASD) and immunodeficiency known as developmental delay, intellectual disability, joint contractures and facial dysmorphism; immunodeficiency; and short stature (DIJOS) syndrome. However, the phenotypic spectrum is not fully defined, and genotype-phenotype associations need to be further studied. Here we report on two unrelated patients with global developmental delay and autistic features and provide detailed clinical information of both patients, including cranial magnetic resonance imaging (MRI), electroencephalography (EEG), metabolic screening, hearing assessment and neurodevelopmental testing. Whole exome sequencing (WES) was performed for potential genetic causes, and candidate variants were verified via Sanger sequencing. Interpretation of variants was performed in accordance with ACMG guidelines. For Patient 1, we detected a de novo pathogenic heterozygous nonsense variant in KDM3B (c.1970C > G, p.Ser657*). The canonical splice-site variant (c.3973-1G > C) in KDM3B that we found in Patient 2 was classified as likely pathogenic. Clinically, Patient 1 had severe developmental retardation, deafness and autistic tilt, whereas Patient 2 had milder retardation and autistic behaviours with normal hearing. The splice-site variant in Patient 2 may disrupt an upstream intron and is predicted to influence splicing, which may elicit nonsense-mediated mRNA decay and contribute a more severe interference, comparatively. Our results broaden the mutational and phenotypic spectrum of KDM3B-related disorder and highlight the phenotypic heterogeneity even in patients with the same type of variant. Functional analysis underscores the importance of KDM3B in neurodevelopment, optic nerve formation and cognition. Additional studies will be required to define the differences in clinical phenotype at the molecular level.

Weill-Marchesani syndrome (WMS) is characterized by severe short stature, joint contractures, tight skin, heart valve and eye anomalies. WMS is caused by biallelic mutations in ADAMTS10, ADAMTS17, or LTBP2, or mono-allelic mutations in FBN1 Because bone growth is driven by chondrocyte proliferation and hypertrophy in the growth plates, the genetics of WMS suggests that the affected extracellular matrix (ECM) proteins contribute to chondrocyte and growth plate function. Here, we show that Adamts10;Adamts17 double knockout (DKO) mice have significant postnatal lethality and exacerbated bone shortening, which correlated with a narrower hypertrophic zone in their growth plates. Potential ADAMTS17 substrates identified by N-terminomics and yeast-2-hybrid screening revealed the ECM proteins fibronectin (FN1) and collagen VI (COL6A2). In primary ADAMTS10- and ADAMTS17-deficient skin fibroblasts, fibronectin deposition was impaired concomitant with aberrant intracellular accumulation of fibrillin-1. These findings support a role for ADAMTS17 in ECM protein secretion and assembly. Mechanistically, ADAMTS17 appears to be a critical regulator of ECM protein secretion or pericellular matrix assembly, whereas ADAMTS10 likely modulates ECM formation at later stages. The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes: Metaphyseal dysplasia without hypotrichosis (MDWH). Cartilage-hair hypoplasia (CHH). Anauxetic dysplasia (AD). CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine, silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family. Diagnosis of a CHH-AD spectrum disorder is established in a proband with characteristic clinical and radiographic findings. If clinical and radiographic findings are inconclusive, identification of biallelic pathogenic variants in RMRP by molecular genetic testing can confirm the diagnosis and allow for family studies. Treatment of manifestations: If cervical spinal instability is identified in a person with AD, special care is required during general anesthesia; surgery may be needed to fuse unstable cervical vertebrae and/or to treat progressive kyphoscoliosis that compromises lung function in AD; corrective osteotomies may be required for progressive varus deformity of the lower extremities; treatment of underlying infections based on their type, location, and severity; immediate high-dose intravenous acyclovir for varicella infection; consideration of prophylactic antibiotic therapy and/or immunoglobulin replacement therapy; recurrent severe infections, severe combined immunodeficiency (SCID), and/or severely depressed erythropoiesis may warrant hematopoietic stem cell transplantation; physiotherapy and other acute and long-term medical management for bronchiectasis per pulmonologist; red blood cell transfusions for severe anemia with iron chelation as needed; standard treatments for malignancies, congenital megacolon, Hirschsprung disease, and intestinal malabsorption; nutritional evaluation in those with short bowel syndrome; hormonal induction as needed for pubertal maturation; developmental and educational support as needed. Surveillance: Monitor growth using CHH-specific growth curves; clinical and (if warranted) radiographic examination of joints of the lower extremities and spine annually in childhood and as required in adulthood; annual clinical and radiographic examination of the spine in individuals with AD. Monitor all children regardless of immune status during the first two years of life for recurrent infections, especially life-threatening varicella infection, then monitor annually; laboratory assessment for those with suspected infection; laboratory assessment of immune function with frequency based on initial lab results; assess the frequency of respiratory tract infections at each visit; high-resolution CT examination for those with suspected bronchiectasis and lung MRI to monitor bronchiectasis. For those who have not had anemia, observe for clinical signs of anemia; for those in remission after treatment, complete blood count every six months. Clinical and laboratory examination for manifestations of malignancy annually in children and as needed in adults; abdominal ultrasound every one to two years in children and as needed in adults. Assess pubertal development annually throughout adolescence; assess for hypogonadism in those with pubertal delay. Developmental and cognitive assessment as needed in those with AD throughout childhood. Agents/circumstances to avoid: Administration of live vaccines when signs of abnormal immunologic function or SCID are present. Evaluation of relatives at risk: Early diagnosis of relatives at risk for the CHH-AD spectrum disorders allows for early management of manifestations that can be associated with significant morbidity (e.g., infections, immunization with live vaccines, malignancies). Pregnancy management: Fetal growth is generally unaffected; therefore, planned cesarean section should be considered in term pregnancies in affected women due to cephalopelvic disproportion. CHH-AD spectrum disorders are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an RMRP pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the RMRP pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and molecular genetic prenatal and preimplantation genetic testing for CHH-AD spectrum disorders are possible.

Glucocorticoids (GCs) are widely prescribed for their anti-inflammatory and immunosuppressive properties; however, prolonged, unsupervised, or over-the-counter (OTC) use, particularly during childhood and adolescence, can have profound consequences. We present a case of an 18-year-old male patient with a 10-year history of self-medicating with oral prednisolone for joint pain, without medical supervision. He presented with severe hip pain and difficulty ambulating. Examination revealed classical Cushingoid features, severe short stature, and delayed puberty. Pelvic radiographs revealed a pathological fracture of the left femoral neck and avascular necrosis (AVN) of the right femoral head. A dual-energy X-ray absorptiometry (DXA) scan demonstrated severe osteoporosis. Hormonal evaluation revealed suppressed 8:00 AM serum cortisol, consistent with secondary adrenal insufficiency. This case underscores the devastating consequences of unregulated GC use during adolescence, resulting in growth failure, delayed puberty, osteoporosis, adrenal insufficiency, and AVN. It highlights the need for clinician vigilance, public education, and policy-level regulation of OTC steroid access to prevent such avoidable endocrinopathies.