Congenital Musculoskeletal DisordersS. Yudha PatriaPediatrics Dept. Fac. Medicine, Gadjah Mada Univ, Yogyakarta

Syndactyly

Limited Movement may due to...PainDecrease ROMUnstable Bone Muscles weakness

Congenital WeaknessCould be problems in:- CNS- Nerves- Myo-neural junction- Muscles- BonesGenetics defect of genetic materials major cause of congenital anomalies

Congenital bone defects: - Achondroplasia- Osteogenesis imperfecta

Congenital Muscle(s) weakness- Myopathies- Muscular dystrophies- Spinal muscle atrophy

AchondroplasiaYudha Patria, MD & PhD

= Chondrodysplasia

Transmitted: autosomal dominant with complete penetrance

De novo mutations cause 75-80% of cases

Incidence: 1 in 15,000 to 1 in 40,000 live births

Occurs in all races and in both sexes same frequency

EtiologyMutations FGFR3 gene (fibroblast growth factor receptor-3 gene)

The gene mapped to 4p16.3

99% G1138A or G1138C mutations G380R amino acid changed

PathophysiologyThe protein (FGFR-3) responds to signals from growth factors (FGF) stimulate cell growth and maturation

Mutated FGFR-3 decreased of: - endochondral ossification - proliferation of chondrocytes in growth plate cartilage, - cellular hypertrophy- cartilage matrix production

The clinical features

Short stature unproportionate type (average final height: male 131 cm; female 124 cm)

Rhizomelic (proximal): short arms and legs Limitation of elbow extension Trident configuration of the hands Genu varum (bow legs) Thoracolumbar gibbus in infancy Exaggerated lumbar lordosis, which develops when walking begins Large head with frontal bossing Normal trunk length

The radiograph of achondroplasia

Narrowing of the interpediculate distance of the caudal spine Notch-like sacroiliac groove Circumflex on the metaphysis

Head USG or brain CT-scan enlargement of ventriclesothers abnormalities

- Genetic analysis: Pedegree analysisGene mutation analysis

ManagementThe follow-up care ( international symposium on achondroplasia):

Growth and head circumference measurements plotted on growth curves standardized for achondroplasiaNeurologic examinations (CT scan, MRI, somatosensory-evoked potentials, and polysomnography )Management of frequent middle ear infections and dental crowding

Genetic counseling

Height for children with achondroplasia

Differential Diagnosis:- Hypochondroplasia (milder form)

- FGFR related Craniostosis Crouzon Syndrome - Thanatophoric dysplasia

- Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)

Crouzon Syndrome

Thanatophoric Dysplasia

Osteogenesis Imperfecta (OI)

Definition

Osteogenesis imperfecta (OI) is a group of genetic diseases of collagen in which the bones are formed improperly, making them fragile and prone to breaking

Collagen is a fibrous protein material, serves as the structural foundation of skin, bone, cartilage, and ligaments

OI

OI results from abnormalities in the collagen gene COL1A1 or COL1A2

In OI type I, II, and III, the gene map locus is 17q21.31-q22, 7q22.1; and type IV map locus is 17q21.31-q22 only

Demographics Affects equal numbers of males and females, and occurs in about one of every 20,000 births. The pattern of inheritance is autosomal dominant

Signs and symptoms

Type I (the most common and mildest type)

Bones are predisposed to fracture, with most fractures occurring before puberty. People with OI type I typically have about 2040 fractures before pubertyStature is normal or near-normalJoints are loose and muscle tone is lowSclera have blue, purple, or gray tintFace shape is triangularTendency toward scoliosis Bone deformity is absent or minimalDentinogenesis imperfecta may occur, causing brittle teeth

Type II

Type II is the most severe form of OI (lethal form)Lethal at or shortly after birth, often as a result of respiratory problemsFractures are numerous and bone deformity is severeStature is small with underdeveloped lungs.Collagen is formed improperly.

Type IIIBones fracture easily (often present at birth), and x rays may reveal healed fractures that occurred before birth. People with OI Type III may have more than 100 fractures before puberty

Stature is significantly shorter than normal

Joints are loose and muscle development is poor in arms and legsRib cage is barrel-shaped.Respiratory problems are possibleBones are deformed (often severe)Hearing loss is possible.Others, similar to type 1

Type IVSymptom falls between Type I and Type III in severity

Bones fracture easily, with most fractures occurring before pubertyStature is shorter than average.Sclera (whites of the eyes) are normal in color, appearing white or near-white.Bone deformity is mild to moderate, scoliosis is likelyRib cage is barrel-shaped

DiagnosisDiagnosis OI often possible solely on clinical features and x ray findings

Diagnosis is suspected when a baby has bone fractures after having suffered no apparent injury

Another indication is small, irregular, isolated bones in the sutures between the bones of the skull (wormian bones)

Collagen or DNA tests may help confirm a diagnosis of OI. These tests generally require several weeks

Congenital Muscular DisordersS. Yudha PatriaDept. Pediatrics

Congenital muscular disorders consist of heterogeneous group muscular diseases genetic abnormality

The major clinical features:- muscle weakness - hyporeflexia - hypotonia - dysmorphic features

Onset infancy and early childhoodNon-progressive, Slow progressive with age Definitive diagnosis Histopathologic in the muscle biopsyTreatment : supportive, gene therapy

Congenital Muscular Disorders

Myopathies Muscular dystrophyChannelopathies

1. Muscular dystrophyA group of inherited, progressive muscle disorders, distinguished clinically by the selective distribution of weakness Include:- Dystrophinopaties (Duchenne & Becker type)- Limbgirdle muscular dystrophy - Facioscapulohumeral muscular dystrophy (Landouzy-Dejerine)

Gower Maneuver

Pseudohypertrophy

Diagnostic TestsBlood CK

EMG myopathy

Muscle biopsy specific (immuno) staining

Genetics tests: Duchenne, Becker, Distal-, some forms of Limb-girdle and Emery-Dreifuss dystrophies

DiagnosisCharacteristic clinical findingsage of onsetfamily history Serum CK elevated (up to 50 to 100 times)supported by electromyographyDifinitive: immunostaining of muscle biopsyMolecular study

Muscle biopsy. A group of necrotic and regenerating muscle fibers is apparent

TreatmentNo specific treatment exists Supportive therapyGene therapy

2. ChannelopathiesNeuromuscular disorders disturbance of the membrane conduction system, resulting from mutations affecting ion channels. Includes:- Myotonic Disorders- Familial periodic paralysis

2.1 MYOTONIC DISORDERS

A group of disorders characterized by abnormally slow relaxation after voluntary muscle contraction due to a muscle membrane abnormality

Includes:- Myotonic dystrophy (Steinert's disease) - Myotonia congenita (Thomsens disease)

2.2 FAMILIAL PERIODIC PARALYSIS A group of rare autosomal dominant disorders characterized by episodes of flaccid paralysis with loss of deep tendon reflexes and failure of muscle to respond to electrical stimulation

Includes:Hypokalemic form Normokalemic formHyperkalemic form

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