Skeletal and Connective Tissue

Classic Ehlers-Danlos syndrome (cEDS) - Clinical Vignette

A child presents with soft, velvety, hyperextensible skin that bruises easily. She has "cigarette paper" scars from minor trauma. Joint hypermobility is present.

Classic Ehlers-Danlos syndrome (cEDS) - Genetics

Autosomal dominant.

Caused by pathogenic variants in COL5A1 or COL5A2 (encoding type V collagen) most commonly; rarely caused by variants in COL1A1.

Classic Ehlers-Danlos syndrome (cEDS) - Key Features

Marked skin hyperextensibility

Atrophic "cigarette paper" scars (papyraceous scarring)

Joint hypermobility

Easy bruising

Soft, doughy skin texture

Molluscoid pseudotumors and subcutaneous spheroids.

Classic Ehlers-Danlos syndrome (cEDS) - Diagnosis

Clinical evaluation combined with confirmatory molecular genetic testing (COL5A1, COL5A2, COL1A1).

Classic Ehlers-Danlos syndrome (cEDS) - Management

Skin protection and meticulous wound closure (low-tension sutures, prolonged support of healing scars)

Joint protection, low-resistance physical therapy, and bracing for hypermobility

Baseline echocardiogram to screen for aortic root dilation

Cardiology and orthopedic referral as needed.

Hypermobile Ehlers-Danlos syndrome (hEDS) - Clinical Vignette

A 25-year-old woman presents with chronic joint pain and recurrent dislocations. She has soft, mildly stretchy skin and scores 7/9 on the Beighton scale. She also reports POTS-like symptoms and functional GI issues.

Hypermobile Ehlers-Danlos syndrome (hEDS) - Genetics

Unknown genetic basis (no causative gene identified; hEDS is the only EDS subtype without a known molecular diagnosis). Likely polygenic or multifactorial with autosomal dominant-like familial clustering.

Hypermobile Ehlers-Danlos syndrome (hEDS) - Key Features

Generalized joint hypermobility (assessed via Beighton score)

Chronic pain and fatigue

Recurrent joint subluxations and dislocations

Mild skin hyperextensibility (less severe than cEDS)

Associated conditions: POTS, functional GI disorders, mast cell activation syndrome

Requires exclusion of other heritable connective tissue disorders.

Hypermobile Ehlers-Danlos syndrome (hEDS) - Diagnosis

Strict clinical diagnostic criteria (2017 International Classification); no molecular test available.

Hypermobile Ehlers-Danlos syndrome (hEDS) - Management

Supportive, multidisciplinary care (no disease-modifying therapy)

Physical therapy emphasizing joint stabilization and low-impact strengthening

Pain management and bracing for recurrent subluxations

Treatment of associated conditions: POTS (fluid/salt loading, compression garments), functional GI symptoms, and mast cell activation syndrome.

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) - Clinical Vignette

A neonate with marked muscle hypotonia and severe joint hypermobility develops progressive kyphoscoliosis over the first year. Sclerae are blue, skin is hyperextensible, and there's a history of microcornea on eye exam. A vascular event (arterial rupture) in adolescence is the family's biggest worry.

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) - Genetics

Autosomal recessive.

Caused by biallelic variants in PLOD1 (encoding lysyl hydroxylase 1; most common, characterized by an elevated urinary deoxypyridinoline/pyridinoline [LP/HP] ratio) or FKBP14 (normal urinary LP/HP ratio, prominent myopathic features and sensorineural hearing loss).

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) - Key Features

Congenital muscle hypotonia (presents at birth, distinguishing it from other EDS subtypes)

Progressive kyphoscoliosis developing within the first year of life

Generalized joint hypermobility with recurrent dislocations

Skin hyperextensibility and easy bruising

Ocular fragility: blue sclerae, microcornea, and risk of globe rupture

Vascular fragility: medium-vessel arterial rupture (key cause of mortality)

Sensorineural hearing loss (more prominent in FKBP14-related kEDS).

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) - Diagnosis

Clinical suspicion based on 2017 international classification (congenital hypotonia + early progressive kyphoscoliosis + generalized joint hypermobility)

Urinary deoxypyridinoline/pyridinoline (LP/HP) ratio analysis for kEDS-PLOD1

Confirmatory molecular genetic testing (sequencing of PLOD1 and FKBP14).

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) - Management

Cardiovascular: baseline and serial vascular imaging (head-to-pelvis MRA every 1-2 years); avoid arterial puncture and contact sports

Spine: orthopedic surveillance, bracing, and surgical correction when severe

Ocular: annual ophthalmology exam and protection against trauma

Audiology surveillance (particularly for FKBP14 variants) High-risk obstetric management during pregnancy (risk of uterine rupture and arterial dissection).

Stickler syndrome - Clinical Vignette

A newborn with Pierre Robin sequence (micrognathia, glossoptosis, cleft palate) fails the newborn hearing screen. Eye exam reveals vitreous abnormalities. Family history reveals a parent with retinal detachment and early arthritis.

Stickler syndrome - Genetics

Autosomal dominant (most common) or autosomal recessive.

Caused by pathogenic variants in fibrillar collagen genes:

Type 1 (COL2A1, most common, membranous vitreous)

Type 2 (COL11A1)

Type 3 (COL11A2, non-ocular form), or autosomal recessive forms (COL9A1, COL9A2, COL9A3).

Stickler syndrome - Key Features

Ocular: high myopia, vitreous abnormalities, and high risk of retinal detachment

Orofacial: Pierre Robin sequence, midface hypoplasia, and cleft palate

Hearing loss (sensorineural and/or conductive)

Skeletal: early-onset osteoarthritis and joint hypermobility

Marfanoid habitus in some individuals.

Stickler syndrome - Diagnosis

Clinical recognition of ocular, orofacial, auditory, and skeletal findings (Pierre Robin sequence is a common presenting clue)

Slit-lamp and dilated fundus examination for vitreous abnormalities (e.g., membranous vitreous in Type 1)

Audiometry for sensorineural and conductive hearing loss

Confirmatory molecular testing of COL2A1, COL11A1, COL11A2, or COL9A1/A2/A3.

Stickler syndrome - Management

Regular ophthalmologic surveillance and prophylaxis to prevent retinal detachment

Audiologic evaluations and hearing amplification as needed

Pierre Robin sequence airway and feeding management (e.g., prone positioning, airway support, cleft palate repair)

Rheumatologic and orthopedic care for early-onset arthropathy.

Vascular Ehlers-Danlos syndrome (vEDS) - Clinical Vignette

A 30-year-old woman presents with sudden abdominal pain. CT reveals a spontaneous sigmoid colon perforation. She has thin, translucent skin with visible veins and a history of a spontaneous arterial dissection.

Vascular Ehlers-Danlos syndrome (vEDS) - Genetics

Autosomal dominant.

Caused by heterozygous pathogenic variants in COL3A1 encoding type III procollagen.

Vascular Ehlers-Danlos syndrome (vEDS) - Key Features

Thin, translucent skin with easily visible subcutaneous veins

Spontaneous arterial rupture or dissection (especially medium-sized arteries)

Spontaneous bowel rupture (most commonly the sigmoid colon)

Uterine rupture during pregnancy Characteristic facial features: thin lips, small chin (micrognathia), pinched nose, and prominent eyes

Minimal skin hyperextensibility (unlike classic EDS); small-joint hypermobility

Reduced median lifespan (~50 years).

Vascular Ehlers-Danlos syndrome (vEDS) - Diagnosis

Clinical suspicion based on major vascular or hollow-organ rupture and family history

Confirmatory molecular genetic testing of COL3A1.

Vascular Ehlers-Danlos syndrome (vEDS) - Management

Avoidance of invasive vascular procedures, arteriography, elective surgery, and collision/contact sports

Medical therapy with celiprolol (or other beta-blockers/ARBs) to reduce vascular events

High-risk pregnancy surveillance and delivery planning

Prompt surgical/endovascular intervention for life-threatening organ or arterial rupture.

Achondroplasia - Clinical Vignette

A prenatal ultrasound at 28 weeks shows shortened long bones (rhizomelic shortening) with a relatively large head and frontal bossing. Parents are average height.

Achondroplasia - Genetics

Autosomal dominant.

Caused by gain-of-function variants in FGFR3 (fibroblast growth factor receptor 3), with c.1138G>A (p.Gly380Arg) accounting for ~98% of cases.

Constitutive receptor activation inhibits chondrocyte proliferation. ~80% of cases are de novo and associated with advanced paternal age.

Achondroplasia - Key Features

Rhizomelic (proximal) limb shortening with short stature (average adult height ~4 feet / 122-132 cm)

Macrocephaly, frontal bossing, and midface hypoplasia

Trident hand configuration Lumbar lordosis and thoracolumbar kyphosis

Normal intelligence

Complications: foramen magnum stenosis (risk of central apnea and sudden infant death), spinal stenosis in adulthood, recurrent otitis media, and obstructive sleep apnea.

Achondroplasia - Diagnosis

Clinical and radiographic recognition (rhizomelic short stature, characteristic facies, trident hands)

Skeletal survey showing short tubular bones, caudal narrowing of lumbar interpedicular distance, squared iliac wings, and "champagne glass" pelvic inlet

Prenatal third-trimester ultrasound showing shortened long bones, macrocephaly, and frontal bossing

Confirmatory targeted FGFR3 molecular genetic testing (p.Gly380Arg).

Achondroplasia - Management

Vosoritide (C-type natriuretic peptide analog) FDA-approved to improve linear growth

Neuroimaging and polysomnography in infancy to screen for foramen magnum stenosis (surgical suboccipital decompression if indicated)

Monitoring and treatment for obstructive sleep apnea and recurrent otitis media

Orthopedic management for spinal stenosis and bowing of the legs.

Campomelic dysplasia - Clinical Vignette

A newborn has bowed femora and tibiae, a bell-shaped chest with short ribs, micrognathia with cleft palate, hypoplastic scapulae, and respiratory distress within hours of birth. External genitalia appear female. Karyotype returns 46,XY. Skeletal survey shows 11 pairs of ribs, small scapulae, and angulated long bones.

Campomelic dysplasia - Genetics

Autosomal dominant (~95% de novo; ~5% recurrence risk due to parental gonadal mosaicism).

Caused by heterozygous loss-of-function variants in SOX9 (17q24.3) or chromosomal rearrangements disrupting its upstream regulatory region.

SOX9 regulates both chondrogenesis and testis determination downstream of SRY.

Campomelic dysplasia - Key Features

Bowed (angulated) long bones, especially the femora and tibiae (absent in the ~10% acampomelic variant)

11 pairs of ribs and severely hypoplastic, wing-like scapulae

Bell-shaped narrow thorax leading to pulmonary hypoplasia

Severe tracheobronchomalacia (leading cause of neonatal mortality)

Craniofacial features: macrocephaly, flat midface, and Pierre Robin sequence (micrognathia, glossoptosis, cleft palate)

46,XY complete or partial sex reversal (~75% of 46,XY infants present with female or ambiguous external genitalia)

Mixed sensorineural and conductive hearing loss.

Campomelic dysplasia - Diagnosis

Prenatal ultrasound showing bowed long bones, narrow thorax, and micrognathia

Postnatal skeletal survey demonstrating 11 pairs of ribs, hypoplastic scapulae, bowed femora/tibiae, and vertically narrow iliac wings

Karyotype in all infants to assess for 46,XY sex reversal SOX9 sequencing, deletion/duplication analysis, and cytogenetic evaluation for upstream regulatory rearrangements.

Campomelic dysplasia - Management

Immediate neonatal airway stabilization (CPAP, intubation, or tracheostomy for severe tracheobronchomalacia)

Multidisciplinary cleft/Pierre Robin team management for feeding and airway

Endocrinology and urology evaluation for 46,XY sex-reversed infants (prophylactic gonadectomy due to gonadoblastoma risk in dysgenetic gonads)

Orthopedic management for limb angulation, scoliosis, and cervical spine instability

Audiologic monitoring and genetic counseling regarding gonadal mosaicism.

Cleidocranial dysplasia - Clinical Vignette

A child can bring his shoulders together in front of his chest ("opposing shoulders"). He has a large head with frontal bossing, delayed closure of fontanelles, and multiple dental abnormalities.

Cleidocranial dysplasia - Genetics

Autosomal dominant.

Caused by heterozygous loss-of-function variants in RUNX2, encoding a transcription factor essential for osteoblast differentiation and bone/cartilage development.

Cleidocranial dysplasia - Key Features

Absent or hypoplastic clavicles allowing hypermobile, "opposing" shoulders Delayed closure of cranial sutures and fontanelles (may remain open into adulthood)

Dental anomalies: supernumerary teeth, retention of deciduous teeth, and delayed eruption of permanent teeth

Mild-to-moderate short stature

Wormian bones on skull radiographs and wide pubic symphysis.

Cleidocranial dysplasia - Diagnosis

Clinical recognition of hypermobile shoulders, open fontanelles, frontal bossing, and dental anomalies

Radiographs showing absent/hypoplastic clavicles, Wormian bones, delayed skull ossification, and wide pubic symphysis

Panoramic dental imaging demonstrating supernumerary and unerupted teeth

Confirmatory RUNX2 sequencing and deletion/duplication analysis.

Cleidocranial dysplasia - Management

Dental and orthodontic care: staged extraction of retained deciduous and supernumerary teeth with surgical exposure of impacted permanent teeth

Cranial protection (protective helmets in infancy when fontanelles are widely open)

Orthopedic surveillance for scoliosis, genu valgum, and joint dislocations

Audiology and ENT follow-up for recurrent otitis media and hearing loss.

Diastrophic dysplasia - Clinical Vignette

A neonate has short-limbed short stature with rhizomelic limb shortening, thumbs that stick out abducted from the hand ("hitchhiker thumbs"), and ears that quickly become swollen and develop a calcified, cauliflower appearance.

Cleft palate is present.

Within months, severe joint contractures and progressive scoliosis develop.

Diastrophic dysplasia - Genetics

Autosomal recessive.

Caused by biallelic pathogenic variants in SLC26A2 (DTDST), encoding a sulfate transporter required for cartilage proteoglycan sulfation.

Allelic with lethal achondrogenesis type 1B, atelosteogenesis type 2, and milder recessive multiple epiphyseal dysplasia.

Diastrophic dysplasia - Key Features

Rhizomelic short-limbed short stature (adult height ~120 cm)

Pathognomonic "hitchhiker thumbs" (proximally placed, abducted thumbs)

"Cauliflower ear" (acute cystic swelling of the pinnae in infancy progressing to calcified deformity in ~80%)

Cleft palate (~50%)

Congenital and progressive joint contractures and clubfoot (talipes equinovarus)

Severe progressive kyphoscoliosis and infantile cervical kyphosis (risk of spinal cord compression)

Normal intelligence.

Diastrophic dysplasia - Diagnosis

Clinical recognition of short-limbed dwarfism, hitchhiker thumbs, and cystic/cauliflower ear deformity

Skeletal survey showing short tubular bones, broad short metacarpals, and vertebral anomalies

Confirmatory molecular genetic testing of SLC26A2.

Diastrophic dysplasia - Management

Cervical spine MRI in infancy and anesthesia precautions due to cervical kyphosis and airway difficulty

Orthopedic management for clubfoot, progressive scoliosis (bracing/surgery), and joint contractures

Surgical repair of cleft palate and airway monitoring

Genetic counseling regarding 25% autosomal recessive recurrence risk.

Hypochondroplasia - Clinical Vignette

A 5-year-old presents for evaluation of short stature (–2 SD). On exam, limbs appear mildly short relative to trunk, hands are short, and lumbar lordosis is mildly increased. Skull and facial features are normal (no frontal bossing, no macrocephaly). Father is also short with similar proportions and was never diagnosed.

Hypochondroplasia - Genetics

Autosomal dominant.

Caused by heterozygous gain-of-function variants in FGFR3 (~50-70% of clinical cases), most commonly p.Asn540Lys (N540K) in the tyrosine kinase domain, resulting in milder constitutive receptor activation than in achondroplasia.

Hypochondroplasia - Key Features

Mild disproportionate short-limbed short stature (adult height typically 130-145 cm, or -2 to -4 SD)

Normal craniofacial appearance (no macrocephaly, frontal bossing, or midface hypoplasia, distinguishing it from achondroplasia)

Mild brachydactyly and mild lumbar lordosis

Absence of severe foramen magnum stenosis

Usually normal cognition (a small subset exhibits mild learning difficulties or temporal lobe epilepsy).

Hypochondroplasia - Diagnosis

Skeletal survey showing short long bones, short broad femoral necks, and squared iliac wings, typically without caudal narrowing of the lumbar interpedicular distance

Molecular genetic testing of FGFR3 (targeting the N540K hotspot or full gene sequencing; clinical diagnosis stands if FGFR3-negative with classic radiographic findings).

Hypochondroplasia - Management

Endocrine monitoring of growth velocity; growth hormone therapy considered case-by-case

Orthopedic care and optional limb-lengthening procedures

Developmental screening and brain MRI/EEG if seizures or cognitive concerns arise

Genetic counseling regarding 50% transmission risk.

Léri-Weill dyschondrosteosis (SHOX deficiency) - Clinical Vignette

A 10-year-old girl with short stature has mesomelic limb shortening (forearms and lower legs) and a visible wrist deformity (Madelung deformity).

Léri-Weill dyschondrosteosis (SHOX deficiency) - Genetics

Pseudoautosomal dominant inheritance.

Caused by heterozygous deletions or pathogenic variants resulting in haploinsufficiency of the SHOX gene (or its regulatory enhancers) located in the pseudoautosomal region 1 (PAR1) of the X and Y chromosomes.

Biallelic loss causes severe Langer mesomelic dysplasia.

Léri-Weill dyschondrosteosis (SHOX deficiency) - Key Features

Mesomelic short stature (disproportionate shortening of the middle limb segments: forearms and lower legs) Madelung deformity of the wrist (dorsal bowing of the radius, prominent ulnar head, and triangular arrangement of carpal bones) Phenotype is more frequent and severe in females than in males.

Léri-Weill dyschondrosteosis (SHOX deficiency) - Diagnosis

Clinical evaluation showing mesomelic short stature and wrist deformity Wrist radiographs demonstrating dorsal radial bowing, triangularization of the distal radial epiphysis, and pyramidal carpal wedging SHOX deletion/duplication analysis (captures most cases, including enhancer deletions) and sequencing Karyotype in females if Turner syndrome is on the differential.

Léri-Weill dyschondrosteosis (SHOX deficiency) - Management

Recombinant human growth hormone (GH) therapy to improve adult height outcomes Orthopedic management (wrist splinting, ergonomics, or surgical osteotomy for painful/limiting Madelung deformity) Growth and skeletal monitoring through adolescence.

Thanatophoric dysplasia - Clinical Vignette

A prenatal ultrasound reveals severe limb shortening, a narrow chest, and macrocephaly with a cloverleaf skull. Polyhydramnios is present. The pregnancy is complicated by hydrops.

Thanatophoric dysplasia - Genetics

Autosomal dominant (virtually 100% de novo). Caused by strongly activating gain-of-function variants in FGFR3 distinct from those in achondroplasia. Type I (curved femora) and Type II (straight femora with cloverleaf skull) correlate with specific FGFR3 mutations.

Thanatophoric dysplasia - Key Features

Perinatal lethal skeletal dysplasia (most common lethal skeletal dysplasia) Profound micromelia (severe limb shortening) with redundant skin folds Narrow, bell-shaped thorax causing lethal pulmonary hypoplasia Macrocephaly, frontal bossing, and craniosynostosis / cloverleaf skull (characteristic of Type II) Curved "telephone receiver" femora (characteristic of Type I) Severe platyspondyly (wafer-thin flattened vertebral bodies).

Thanatophoric dysplasia - Diagnosis

Prenatal ultrasound showing severe micromelia, narrow thorax, macrocephaly, polyhydramnios, "telephone receiver" femora (Type I), or cloverleaf skull (Type II) Postnatal radiographs demonstrating severe platyspondyly, short ribs, and short bowed tubular bones Confirmatory FGFR3 molecular genetic testing.

Thanatophoric dysplasia - Management

Palliative and comfort care in the perinatal period; goals-of-care counseling with the family Prenatal counseling and delivery planning (noting obstetric considerations for macrocephaly) Genetic counseling regarding low recurrence risk (small residual risk due to parental gonadal mosaicism).

Hypophosphatasia - Clinical Vignette

A neonate presents with severe skeletal undermineralization, respiratory distress, and hypercalcemia. Alkaline phosphatase level is very low. The baby has "punched out" lesions on skull X-ray.

Hypophosphatasia - Genetics

Autosomal recessive (severe perinatal/infantile forms) or autosomal dominant (milder childhood/adult/odonto forms). Caused by loss-of-function variants in ALPL encoding tissue-nonspecific alkaline phosphatase (TNSALP).

Hypophosphatasia - Key Features

Defective bone and tooth mineralization with characteristically LOW serum alkaline phosphatase (ALP) Elevated TNSALP substrates: serum pyridoxal 5'-phosphate (PLP, vitamin B6) and urine phosphoethanolamine (PEA), plus inorganic pyrophosphate (PPi) accumulation Perinatal/infantile forms: profound skeletal undermineralization, rachitic chest, respiratory failure, hypercalcemia/nephrocalcinosis, craniosynostosis, and vitamin B6-responsive seizures Childhood form: premature loss of deciduous teeth (<5 years old) with intact roots, rickets, and short stature Adult form: osteomalacia, recurrent poorly healing metatarsal stress fractures, pseudofractures, and chondrocalcinosis/pseudogout.

Hypophosphatasia - Diagnosis

Persistently low age- and sex-adjusted serum alkaline phosphatase (ALP) activity Elevated serum pyridoxal 5'-phosphate (PLP) and urinary phosphoethanolamine (PEA) Radiographs showing generalized undermineralization, rachitic metaphyseal changes, and "punched out" skull lucencies Confirmatory molecular genetic testing of ALPL.

Hypophosphatasia - Management

Enzyme replacement therapy with asfotase alfa (bone-targeted recombinant TNSALP), especially in perinatal, infantile, and severe childhood-onset disease Pyridoxine (vitamin B6) for B6-responsive seizures in severe infantile forms Management of hypercalcemia (hydration, dietary calcium restriction) and monitoring for craniosynostosis Dental care to preserve dentition and orthopedic support for fractures/osteomalacia (avoid bisphosphonates, which worsen undermineralization).

Osteogenesis imperfecta (OI) - Clinical Vignette

A newborn has multiple fractures noted at birth, including healing rib fractures suggesting prenatal injury. The baby has blue sclerae. Family history reveals the father has had multiple fractures and hearing loss.

Osteogenesis imperfecta (OI) - Genetics

Autosomal dominant in ~90% of cases, caused by pathogenic variants in COL1A1 or COL1A2 (encoding type I collagen chains). Type I (mild) results from quantitative defects (null alleles reducing normal collagen amount), whereas Types II-IV result from qualitative structural defects (e.g., glycine substitutions disrupting the triple helix). Rare autosomal recessive forms involve collagen-modifying genes (CRTAP, P3H1/LEPRE1, PPIB).

Osteogenesis imperfecta (OI) - Key Features

Recurrent bone fractures with minimal or no trauma and bowing of long bones Blue-gray sclerae (most prominent in Types I and II) Dentinogenesis imperfecta (opalescent, fragile teeth, especially in Types III and IV) Progressive conductive and/or sensorineural hearing loss beginning in young adulthood Wormian bones on skull radiographs and short stature Clinical spectrum ranges from mild (Type I) and moderate/deforming (Types IV and III) to perinatal lethal with crumpled bones and rib fractures (Type II).

Osteogenesis imperfecta (OI) - Diagnosis

Clinical and radiographic evaluation (low-trauma fractures, osteopenia, long-bone bowing, Wormian bones) Molecular genetic testing of COL1A1 and COL1A2 (and recessive OI panel if negative) Careful differentiation from non-accidental trauma (child abuse) in infants presenting with unexplained fractures.

Osteogenesis imperfecta (OI) - Management

Intravenous or oral bisphosphonate therapy (e.g., pamidronate, zoledronic acid) to increase bone mineral density and reduce fracture rate Orthopedic care including intramedullary telescopic rodding of long bones and fracture stabilization Physical and occupational therapy to promote safe mobility and muscle strength Dental care for dentinogenesis imperfecta and audiologic monitoring for hearing loss.

Congenital contractural arachnodactyly (CCA/Beals syndrome) - Clinical Vignette

A newborn has long, slender fingers (arachnodactyly), multiple joint contractures, and "crumpled" ears. The baby has a Marfanoid appearance but no lens dislocation.

Congenital contractural arachnodactyly (CCA/Beals syndrome) - Genetics

Autosomal dominant. Caused by heterozygous pathogenic variants in FBN2 encoding fibrillin-2 (paralogous to FBN1 in Marfan syndrome).

Congenital contractural arachnodactyly (CCA/Beals syndrome) - Key Features

Arachnodactyly (long, slender fingers and toes) and marfanoid habitus Congenital flexion contractures of large and small joints (knees, elbows, hips, fingers) that typically improve with age Characteristic "crumpled" or folded upper helices of the external ears Progressive kyphoscoliosis Absence of ectopia lentis (lens dislocation) and minimal/mild cardiovascular involvement (distinguishing it from Marfan syndrome).

Congenital contractural arachnodactyly (CCA/Beals syndrome) - Diagnosis

Clinical recognition of marfanoid habitus, arachnodactyly, congenital contractures, and crumpled ears Baseline echocardiogram and ophthalmologic exam to distinguish from Marfan syndrome Confirmatory molecular genetic testing of FBN2.

Congenital contractural arachnodactyly (CCA/Beals syndrome) - Management

Early physical therapy and splinting for congenital joint contractures (which generally improve over time) Orthopedic surveillance and bracing/surgery for progressive kyphoscoliosis Periodic echocardiographic monitoring for mild aortic root dilation.

Hereditary multiple exostoses (HME) - Clinical Vignette

A 10-year-old boy has multiple bony lumps near the ends of his long bones, particularly around the knees. X-rays show multiple osteochondromas. His father has similar lesions.

Hereditary multiple exostoses (HME) - Genetics

Autosomal dominant. Caused by loss-of-function variants in the tumor suppressor genes EXT1 (60-70%) or EXT2 (20-30%), which encode glycosyltransferases required for heparan sulfate biosynthesis.

Hereditary multiple exostoses (HME) - Key Features

Multiple benign cartilage-capped bony outgrowths (osteochondromas/exostoses) arising from the metaphyses of long bones (especially around the knees, proximal humerus, and ribs/pelvis) Limb-length discrepancy, angular bowing deformities (e.g., forearm shortening, genu valgum), and mild short stature Pain and mechanical impingement on adjacent nerves, tendons, or vessels ~1-5% lifetime risk of malignant transformation into secondary peripheral chondrosarcoma.

Hereditary multiple exostoses (HME) - Diagnosis

Radiographs showing two or more metaphyseal osteochondromas whose cortex and medullary cavity are continuous with the underlying host bone Molecular genetic testing (sequencing and deletion/duplication analysis) of EXT1 and EXT2 MRI evaluation of lesions showing new pain or growth after skeletal maturity (cartilage cap thickness >1.5-2 cm raises concern for chondrosarcoma).

Hereditary multiple exostoses (HME) - Management

Surgical excision of symptomatic osteochondromas causing pain, neurovascular compression, or joint restriction Orthopedic procedures for limb-length discrepancy and angular limb deformities Lifelong clinical and imaging surveillance for malignant transformation to chondrosarcoma (especially for lesions growing or becoming painful in adulthood).

Nail-patella syndrome (Fong disease) - Clinical Vignette

A 9-year-old is referred for recurrent knee dislocations. The thumbnails are small and split with triangular lunulae, the fifth fingernails look normal, and the elbows do not fully extend. A pelvic radiograph ordered for hip pain shows bilateral conical bony projections off the posterior iliac wings. Urinalysis shows 2+ protein.

Nail-patella syndrome (Fong disease) - Genetics

Autosomal dominant (~20% de novo; complete penetrance with variable intrafamilial expressivity). Caused by haploinsufficiency of LMX1B (9q33.3), encoding a LIM-homeodomain transcription factor essential for dorsal-ventral limb patterning and glomerular basement membrane development.

Nail-patella syndrome (Fong disease) - Key Features

Classic clinical tetrad: nail dysplasia, patellar aplasia/hypoplasia, elbow dysplasia, and iliac horns Nail dysplasia (~98%): hypoplastic, split, or ridged nails with a radial-to-ulnar severity gradient (thumbs most severely affected) and pathognomonic triangular lunulae Patellar hypoplasia or aplasia (~90%) with recurrent lateral knee subluxation/dislocation Elbow dysplasia (~90%) with limited extension/supination and radial head hypoplasia Bilateral posterior iliac horns (~70%): asymptomatic, pathognomonic conical bony projections on pelvic X-ray LMX1B nephropathy (30-50%): proteinuria and hematuria progressing to end-stage kidney disease in 5-15% Increased risk of early-onset primary open-angle glaucoma and ocular hypertension.

Nail-patella syndrome (Fong disease) - Diagnosis

Clinical recognition of the nail/skeletal tetrad plus pelvic radiograph demonstrating bilateral posterior iliac horns Confirmatory LMX1B sequencing and deletion/duplication analysis Renal biopsy (if performed) shows a "moth-eaten" glomerular basement membrane with ectopic fibrillar type III collagen on electron microscopy.

Nail-patella syndrome (Fong disease) - Management

Annual urinalysis (urine protein-to-creatinine ratio) and blood pressure screening starting at diagnosis; ACE inhibitor or ARB therapy for proteinuria Annual ophthalmologic screening with intraocular pressure measurement for glaucoma starting in adolescence Orthopedic care, physical therapy, and bracing for patellar instability and elbow dysfunction Genetic counseling regarding 50% autosomal dominant recurrence risk.

Kniest dysplasia - Clinical Vignette

A child has disproportionate short-trunk short stature, severely restricted joint motion with prominent knees and elbows, midface hypoplasia with cleft palate, high myopia, and progressive sensorineural hearing loss. Skeletal survey shows dumbbell-shaped femora; cartilage histology shows a "Swiss cheese" appearance.

Kniest dysplasia - Genetics

Autosomal dominant (mostly de novo; ~5% recurrence risk from parental gonadal mosaicism). Caused by heterozygous dominant-negative variants (typically exon-skipping splice site variants or small in-frame deletions) in COL2A1 encoding type II collagen.

Kniest dysplasia - Key Features

Disproportionate short-trunk short stature with platyspondyly and kyphoscoliosis Severe progressive joint stiffness/contractures with enlarged, prominent "knobby" joints (especially knees and elbows) Radiographs showing splayed, "dumbbell-shaped" femora and coronal clefts of vertebrae Cartilage histology demonstrating a characteristic "Swiss cheese" appearance due to large chondrocyte vacuoles and disrupted matrix Midface hypoplasia and cleft palate (~50%) Severe early-onset myopia, vitreoretinal degeneration, and high risk of retinal detachment Conductive and sensorineural hearing loss.

Kniest dysplasia - Diagnosis

Clinical and radiographic findings (short-trunk dwarfism, knobby joints with restricted mobility, platyspondyly, dumbbell-shaped femora) Confirmatory molecular genetic testing of COL2A1.

Kniest dysplasia - Management

Baseline and lifelong serial dilated ophthalmologic examinations to prevent/treat retinal detachment Serial audiologic evaluations and hearing support Orthopedic care and physical therapy for joint contractures and kyphoscoliosis Strict anesthesia precautions for difficult airway (midface hypoplasia) and odontoid hypoplasia/cervical spine instability Cleft palate team management and genetic counseling.

Roberts syndrome (SC phocomelia) - Clinical Vignette

A neonate is born with symmetric tetraphocomelia (severe shortening of all four limbs with hands and feet attached close to the trunk), bilateral cleft lip and palate, microcephaly, and a midfacial capillary hemangioma. Karyotype with standard Giemsa staining shows the diagnostic finding: premature centromere separation with characteristic "railroad track" appearance of chromosomes and "puffing" of heterochromatic regions.

Roberts syndrome (SC phocomelia) - Genetics

Autosomal recessive cohesinopathy. Caused by biallelic loss-of-function variants in ESCO2, encoding an N-acetyltransferase that acetylates the SMC3 subunit of the cohesin complex during S-phase to establish sister chromatid cohesion.

Roberts syndrome (SC phocomelia) - Key Features

Symmetric limb reduction defects ranging from tetraphocomelia (hands/feet attached close to the trunk) to milder radial-ray defects (SC phocomelia), with upper limbs more severely affected than lower limbs Craniofacial anomalies: bilateral cleft lip and palate, micrognathia, hypertelorism, midfacial capillary hemangioma, and sparse silvery-blond hair Severe prenatal and postnatal growth retardation and microcephaly Variable intellectual disability and congenital cardiac, renal, or genital anomalies Pathognomonic cytogenetic finding: premature centromere separation (PCS) producing a "railroad track" chromosome appearance and heterochromatin "puffing".

Roberts syndrome (SC phocomelia) - Diagnosis

Cytogenetic karyotype analysis with standard Giemsa or C-banding demonstrating premature centromere separation (PCS) and heterochromatin repulsion/puffing Confirmatory molecular genetic testing (sequencing and deletion/duplication analysis) of ESCO2.

Roberts syndrome (SC phocomelia) - Management

Multidisciplinary supportive care tailored to limb, craniofacial, and organ anomalies Surgical repair of cleft lip and palate and early feeding support Orthopedic, prosthetic, and rehabilitative interventions to maximize limb function and mobility Echocardiography, renal ultrasound, and developmental therapies Genetic counseling regarding 25% autosomal recessive recurrence risk and prenatal diagnosis.