Syndromes: skeletal & sex Flashcards by Annelise Mah

What kind of shortening is rhizomelic

Proximal

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Spondyloepiphyseal dysplasia, early arthritis, retinal detachment, myopia, cataract, hearing loss, Robin sequence

Stickler syndrome: AD, COL2, COL9, COL11 (abnormal structural collagen)

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Knee/hip pain in childhood, need large joint replacement in 30s. Short for family, ragged growth plates on XR.

Multiple epiphyseal dysplasia: AD, COL9, COMP, MATN3 (abnormal structural collagen)

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Limb shortening, hitchhiker’s thumb, boxer/cauliflower ears, spinal deformity, early OA, joint contractures

Diastrophic dysplasia: AR, SLC26A2 (IEM of cartilage/sulfate metabolism)

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Short fingers, nasomaxillary hypoplasia, stippled epiphyses; mild/minimal

Chondrodysplasia punctata: XL, ARSE (IEM of cartilage metabolism)

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Rhizomelic short stature, macrocephaly, midface hypoplasia, frontal bossing, trident hands, genu varum (bow legs), joint hyperextensibility

Achondroplasia: AD GOF of FGFR3, limits cartilage formation/ossification

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Complications of achondroplasia in infancy

Hydrocephalus, hypotonia, motor delay, poor drainage of Eustachian tubes, OSA from large adenoid/tonsils & midface hypoplasia + central apnea from foramen magnum narrowing –> 7.5% mortality of apnea

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Complications of achondroplasia in childhood/adulthood

Craniocervical junction compression, obesity, back pain (exaggerated lumbar lordosis), spinal stenosis, dental crowding, cardiovascular disease (interestingly no T2DM or arthritis).

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Cloverleaf skull, micromelia, short limbs, usually fatal from lung underdevelopment

Thanatophoric dysplasia: AD GOF in FGFR3 (p.Lys650Glu)

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Bowed long bones, narrow iliac wings, Robin sequence, pulmonary hypoplasia, 2/3 of male w/ambiguous genitalia

Campomelic dysplasia: AD, SOX9

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Variant for achondroplasia vs hypochondroplasia

m.1138G>A, p.Gly380Arg // m.1620C>A or G, p.Asn540Lys

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Cataracts, coronal defects of vertebrae, rhizomelia, chondrodysplasia punctata

Rhizomelic chondrodysplasia punctata types 1-3: AR PEXY7, GNPAT, AGPS (peroxisomal)

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Rhizomelia, coronal clefts of vertebral bodies, cataracts, male lethal

Chondrodysplasia punctata type 2 aka Conradi-Hunerman syndrome: XD, CDPX2 (peroxisomal/cholesterol synthesis)

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Short forearm w/Madelung deformity (curved radius w/step-off at wrist), limited mobility, tibiofibular shortening, short stature. Usually female > male but only short stature w/Turner syndrome…

Leri Weill dysostosis: haploinsufficiency for SHOX or SHOXY, usually with X-chromosome deletion

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Aplasia/severe hypoplasia of ulna and fibula, thickened/curved radius and tibia, hypoplasia of mandible

Langer Mesomelic Dysplasia: total KO of SHOX or SHOXY. Very rare.

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Absent ossification of lateral parts of clavicles, wide fontanelles and sagittal suture, low bone density.

Cleidocranial dysplasia: Runx2/CBFA1 (osteoblast)

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Benign cartilage-capped tumors (osteochondromas); stop forming once growth plate closed, malignant transformation ~1%/year

Hereditary multiple exostoses: AD, EXT1 or EXT2

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Osteochondromas + enchondromas

Metachrondromatosis: AD, PTPN11

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Fibrous dysplasia of bone (one or many bones), bone pain, pathologic fracture

Somatic mutations in GNAS1

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Cafe-au-lait spots w/jagged coastal borders, hyperfunctional endocrine disorders (precocious puberty, hyperthyroidism, excess GH, Cushing syndrome), fibrous dysplasia of bone

McCune-Albright Syndrome: somatic mutations in GNAS1

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Multiple fractures, blue sclerae

Osteogenesis imperfecta: AD COL1A1 and 1A2, many AR forms

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Osteosclerosis of whole skeleton within months, macrocephaly, frontal bossing, craniosynostosis, hypodontia/malformed teeth +/- hydrocephalus, CN compression (blind/deaf).
Neuronopathic form with seizures, DD, degeneration of retinal/CNS.

Osteopetrosis, caused by defects in mechanisms for osteoclast acidification and digestion of bone.
Infantile malignant: AR TCIRG1, CLCN7 (Cl channel), OSTM1 (neuropathic form)

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Short limbs, short stature, obtuse mandibular angle w/convex nasal ridge, osteosclerosis w/bone fragility, delayed closure of cranial sutures, clavicular dysplasia

Pycnodysostosis: AR, CTSK (cathepepsin K)

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Later osteopetrosis presentations genes

Intermediate: CLCN7, PLECKHM1, TNFS11 (RANKL)
Late-onset: CLCN7, LRP5
With RTA: AR CA2 (carbonic anhydrase)

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Tx of osteopetrosis

Bone marrow transplant to replace osteoclasts (not for neuronopathic form, often OSTM1)

Sertoli vs Leydig cells

Sertoli: spermatogenesis, secrete Mullerian inhibiting factor locally Leydig: hCG receptors, secrete testosterone locally for Wolffian ducts, external genitalia

Needed for testicular development

SRY

Needed for male external genitalia development

5a reductase changing testosterone -> circulating DHT until puberty

Syndromes associated with ambiguous genitalia w/dysmorphic features

SLO, campomelic dysplasia, mixed gonadal dysgenesis

46,XY with ambiguous genitalia

Androgen insensitivity 5-alpha reductase deficiency DAX1 duplication SF1

Normal or dysgenic testis + streak gonad, external genitalia variable, may have short webbed neck, low-set ears, short stature, edematous hands/feet

Mixed gonadal dysgenesis: mosaic 45X/46XY

DD, ambiguous genitalia, 2-3 toe syndactyly

Smith-Lemli-Opitz: 7-dehydrocholesterol reductase deficiency (low testosterone)

Streak gonads, nephrotic syndrome, 46XY with female organs, no testosterone

Frasier syndrome: WT1 splice site mutations

Male w/ambiguous genitalia, Wilms tumor, congenital nephropathy

Denys-Drash syndrome: WT1 missense

Adrenal insufficiency and 46,XY with sex reversal

SF1 - transcription factor that affects MIF amongst other genes

Congenital adrenal hypoplasia, hypogonadotrophic hypogonadism, don't go through puberty (due to decreased gonad, adrenal, and pituitary development)

DAX1 loss of function; can have Xp21 continuous gene deletion syndrome w/Duchenne muscular dystrophy, glycerol kinase deficiency with DD. (Note DAX1 duplication has ambiguous genitalia)

46XY with female external genitalia but no ovaries/uterus, +testicles w/high circulating androgens

Androgen insensitivity, XR Complete - totally female in appearance Partial - some masculinization/ambiguous genitalia

46XY with ambiguous external genitalia that virilize at puberty, normal internal male structures

5-alpha reductase deficiency, AR

46XX with virilized external genitalia, decreased cortisol +/- salt wasting (decreased aldosterone)

Congenital adrenal hyperplasia (blockade in steroid synthesis -> androgen excess): AR 21-hydroxylase deficiency; if LOF with deletion/nonsense/recombination with pseudogene --> salt wasting.

Presence of both mature ovarian and testicular tissue (45% w/ovotestis), usually ambiguous genitalia but may be normal

Ovotesticular DSD (true hermaphrodism): etiology unknown, some 46XX+SRY, 1/3 mosaic XX/XY

Anogenital ratio

Anus-posterior fourchette / anus-base of clitoris, if >0.5 likely virilized

Which percursor is elevated with 21-hydroxylase deficiency?

17-hydroxyprogesterone

Skin hyperextensibility + joint hypermobility; minor criteria w/bruising, soft skin, atrophic scars/delayed wound healing, hernias

Classical EDS: AD, COL5A1, COL5A2, rarely COL1A1; "Classical-like" AR TNXB, ACLP w/cardiac findings

Acrogeria (aged appearance), spontaneous rupture of arteries, intestines, uterus

Vascular EDS: AD (50% de novo), COL3A1.

Joint laxity, hypotonia, scleral fragility, marfanoid w/ progressive kyphoscoliosis

Kyphoscoliotic EDS: AR, PLOD1 (lysyl hydroxylase, modifies collagen), FKBP14 (+ hearing loss & vascular rupture)

Skeletal dysplasia, hypermobile joints, blue sclerae + some with progeroid appearance

Spondylodysplastic EDS: AR, B4GALT7, B3GALT6, SCL39A13 (Zn transporter). Very rare.

Extreme multiple joint laxity w/difficulty weight bearing, congenital hip dislocation, fractures, scoliosis, short, hyperextensible skin

Arthrochalasia EDS: AD, COL1A1, COL1A2 (usually loss of exon 6, loss of cleavage site)

Sagging skin, hernias, blue sclerae, short stature, short fingers, joints lax but don't sublux, risk of organ rupture

Dermatosparaxis EDS: AR, ADAMTS2 (peptidase). Very rare

High trypase, EDS symptoms + systemic venom reaction, flushing/pruritis, urticaria, anaphylaxis, retained primary teeth

Hereditary Alpha Tryptasemia: duplication or triplication of TPSAB1. Treat with omulizumab.

Aortic aneurysms, arterial tortuosity, dissections, bifid uvula, cleft palate, hyperteloric, C-spine instability

Loeys-Dietz: AD, TGFBR 1/2, SMAD 2/3, TGFB 2/3

Marfan diagnostic criteria

1) Aortic aneurysm + ectopia lentis 2) Aortic aneurysm + FBN1 variant 3) Aortic aneurysm + systemic score ≥7 4) Family history + ectopic lentis OR systemic score 5) Family history + aortic aneurysm

Marfan systemic signs (≥7/20 points needed)

Wrist/thumb sign, pectus, hind foot deformity, pes planus, PTX, dural ectasia, protrusio acetabulum, decreased upper:lower segment, increased arm span, scoliosis, reduced elbow extension, facial features, skin striae, myopia, MVP

Contractures, joint laxity, arachnodactyly, pulmonary emphysema, aortic dilatation w/valvular dysplasia, early death

Neonatal Marfan, due to variants in axons 24-27, 31-32 of FBN1

Marfan appearance without ectopic lentis, congenital contractions, severe aortic dilatation w/o dissection, crumpled ears

Congenital contractural arachnodactyly: AD, FBN2

Craniosynostosis, hypotonia, marfanoid features incl aortic dilatation, no arterial tortuosity, LD/ID

Spritzen Goldberg Syndrome: AD, SKI

Dilatation of ascending aorta w/dissections, no other systemic findings of CTD.

TAAD: 20% genetic incl TGFBR 1/2, ACTA2, MYH11, SMAD3...rarely FBN1

What sutures prematurely fuse in trigonocephaly?

Metopic sutures

What sutures prematurely fuse in brachycephaly (short)?

Bilateral coronal sutures

What sutures prematurely fuse in scaphocephaly (narrow & long)?

Saggital sutures

What sutures prematurely fuse in turricephaly (tall & narrow)?

Coronal +/- lambdoid

Coronal synostosis or macrocephaly, high forehead, hypertelorism, midface hypoplasia, downturned PF, hearing loss, DD, carpal/tarsal fusions

Muenke syndrome: FGFR3 P250R

Rhizomelic shortening, midface hypoplasia, syndactyly, fused cerebral vertebrae, cleft palate, bifid uvula, abnormal corpus callosum and/or gyri, cognitive impairment

Apert syndrome: AD, FGFR2

Craniosynostosis (various sutures), proptosis w/shallow orbits, mandibular prognathism, C-spine abnormalities, normal intellect, risk of intracranial hypertension

Crouzon: AD, 50% sporadic. FGFR2, some overlap w/Pfeiffer

Variable: Mod midface hypoplasia -->cloverleaf skull or turribrachycephaly, broad thumbs/toes, syndactyly of hands.

Pfeiffer syndrome: FGFR1 (P252R), FGFR2 some overlap w/Crouzon

Craniosynostosis, ptosis, small ears, low frontal hairline, duplicated hallux, syndactyly; +/- ID

Saethre-Chotzen: AD, TWIST1 (TF)

Clover leaf skull, short stature, obesity, poly/syndactyly, low-set ears, down slanting PF, hypogonadism

Carpenter syndrome: AR, RAB23 (vesicle transport)

Craniosynostosis + radial defects

Baller Gerold syndrome: AR, RECQL (DNA helicase)

Craniosynostosis + urogenital anomalies, joint contractures, ambiguous genitalia

Antley-Bixler syndrome: CYP450 reductase

Trigonocephaly, microcephaly, up slanting eyes, macrostomia, short stature, CHD, polydactyly, transverse limb reductions, short limbs, hypotonia, seizures, DD, skin laxity

Optiz C syndrome: AD, CD96 (IG superfamily)

Craniosynostosis, developmental delay, marfanoid connective tissue, maxillary hypoplasia, ptosis

Shprintzen-Goldberg syndrome: AD, FBN1 or SKI

Craniosynostosis, hypertelorism, bifid nasal tip, grooved nails, wiry hair, thoracic abnormalities

Craniofrontonasal syndrome: XD, Ephrin B. Males just w/hypertelorism?

Syndromes: skeletal & sex Flashcards

(71 cards)