DWARFISMFITRI APRILLIA, 030.10.108KEPANITERAAN KLINIK ILMU BEDA, RSUD BUDHI ASIH, JANUARI MARET 2015

CONTENTSBackgroundDwarfismClassifications of DwarfismConstitutional Bone DwarfismSkeletal DysplasiaAchondroplasiaThanatophoric DwarfismKniest SyndromeSpondyloepiphyseal DysplasiaDiastrophic Dwarfism

CONTENTSMetabolic Bone DwarfismMucopoysaccharidosesHurler SyndromeHunter SyndromeSan Filippo SyndromeMorquio Syndrome

INTRODUCTIONDwarfism is a commonly used term for disproportionately short stature, although a more medically appropriate term for this disorder is skeletal dysplasia. Little People of America (LPA) defined the Dwarfism as an adult height of 4 feet 10 inches or under, as a result of a medical or genetic conditionAmong the 500 or so known diseases related to dwarfism, there are main groups depending on which physiological mechanism is involvedConstitutional Bone DwarfismMetabolic Bone DwarfismSecondary Bone Dwarfism

OSTEOLOGY

OSTEOLOGYThe skeleton is divided into 2 anatomic regions: axial and appendicular

The axial skeleton includes the bones of the skull, cervical vertebrae, thoracic vertebrae, ribs, sternum, lumbar vertebrae, and the sacrum and coccyxThe appendicular skeleton comprises the extremities, which are paired mirror images of each other;Upper extremityLowe extremity and pelvis

Axial and appendicular skeletal systems. Axial skeleton is green, appendicular skeleton is purple

OSTEOLOGYAlthough often thought of as a static support structure, the skeletal system is a dynamic organ with many functions :

Bones are dynamic structures that are undergoing constant change and remodeling in response to the ever-changing environmentGiving us our human shapeAllowing locomotion and motor functionFacilitating respiration, protecting vital organsProducing marrow-derived cells, andPlaying a crucial role in homeostatis

In fact, there is so much turnover that in 4 years, the skeleton of a young person will be completely new as compared with their skeleton today

OSTEOLOGYENDOCHONDRIAL OSSIFICATION

OSTEOLOGYENDOCHONDRIAL OSSIFICATION

OSTEOLOGYENDOCHONDRIAL OSSIFICATION

OSTEOLOGYEndochondral ossification of long bones through cartilage precursor.

OSTEOLOGYBones can be divided into 3 generic groups:

Long bones

Formed from a cartilage model precursor by endochondral ossificationShort bones

Arise from the same precursors but are not necessarily structurally similar to long bones, often taking on unique shapesFlat bones

Formed without a precursor by intramembranous ossification and can have unusual shapes (eg, skull or sternum)

OSTEOLOGYLONG BONESMature long bones have 3 distinct zones: epiphysis, metaphysis, and diaphysis

OSTEOLOGYSHORT BONESShort bones are also formed by the same cartilage precursor model as long bonesThey tend to have unique shapes and functionsThey provide less overall height than long bonesThey vary in size and shape

OSTEOLOGYFLAT BONESStemming from mesenchymal tissue sheets, flat bones never go through a cartilaginous modelAlthough similar to the previously mentioned bones in some respects, flat bones differ completely in their embryologic origin

DWARFISM

DEFINITION OF DWARFISMRestricted growth or Dwarfism is a condition characterized by short stature. It can be caused by several different medical conditions.Dwarfism is generally defined as an adult height of 4 feet 10 inches (147 centimeters) or less. The average adult height among people with dwarfism is 4 feet (122 cm), defined by the advocacy group Little People of America (LPA).There are two types of Dwarfism:

Proportionate dwarfism (proportionate short stature/PSS)Disproportionate dwarfism (disproportionate short stature/DSS)

PROPORTIONATE DWARFISMPSS results from medical conditions present at birth or appearing in early childhood that limit overall growth and development. So the head, trunk and limbs are all small, but theyre proportionate to each other.Many of them result in poor development of one or more body systems because the disorders affect overall growth.Growth hormone deficiency is a relatively common cause. Signs include:Height below the third percentile on standard pediatric growth chartsGrowth rate slower than expected for ageDelayed or no sexual development during the teen years

DISPROPORTIONATE DWARFISMIf body size is disproportionate, some parts of the body are small, and others are of average size or above-average.Disorders causing DSS inhibit the development of bonesAlmost all people with DSS have normal intellectual capacities.

The most common cause of DSS is a disorder called achondroplasia and muchopolysacharidosis that causes disproportionately short stature.

CLASSIFICATION OF DWARFISM

CLASSIFICATION OF DWARFISMConstitutional Bone Dwarfism. These types of dwarfism cause growth and developmental abnormalities in bones and cartilageMetabolic Bone Dwarfism. When the metabolism of calcium, phosphorous, carbohydrates, and fats is flawed, bone growth and structure may be affectedSecondary Bone Dwarfism. Bone disorders play a role in the diagnosis of these types of dwarfism, but their symptoms are secondary. (Turner Syndrome)

CONSTITUTIONAL BONE DWARFISM

CONSTITUTIONAL BONE DWARFISMConstitutional Bone Dwarfism results in childhood short stature but relatively normal adult height. Children with CDGP are usually have normal size at birth. However, a downward shift in growth rate begins at three to six months of age that is parallel to that seen in most normally growing children in this age groupThese types of dwarfism cause growth and developmental abnormalities in bones and cartilage. They also affect skeletal structure and morphology

CONSTITUTIONAL BONE DWARFISMSkeletal DysplasiaAchondroplasiaThanatophoric DwarfismKniest SyndromeSpondyloepiphyseal DysplasiaDiastrophic Dwarfism

SKELETAL DYSPLASIA

Abnormal shape and size of skeletal dysplasia

PATHOPHYSIOLOGY OFSKELETAL DYSPLASIAAre a heterogeneous group of more than 200 disorders characterized by abnormalities of cartilage and bone growth.

Resulting in abnormal shape and size of the skeleton and disproportion of the long bones, spine and head.

Skeletal dysplasias are caiused by widespread disturbance of bone growth, beginning during the early stages of fetal development and evolving throughout life due to active gene involvement.

PATHOPHYSIOLOGY OFSKELETAL DYSPLASIABased on the underlying molecular genetic cause, the dysplasias can be broadly grouped by the function of the protein product of the causative gene. This type of classification is clinically useful because many of the disorders caused by genes whose protein products have similar functions also share clinical characteristics.

Skeletal Dysplasias differ in natural histories, prognoses, inheritance patterns, and etiopathogenetic mechanisms.

PATHOPHYSIOLOGY OFSKELETAL DYSPLASIAResting zone of the growth plate: SOX9 gene mutation causes camptomelic dysplasia

Examples of genes that play a role in growth plate chondrocytes and skeletal dysplasia include the following: Proliferation zone of the growth plate: FGFR3 gene mutation causes achondroplasia, hypochondroplasia, and thanatophoric dysplasia

Hypertrophic zone of the growth plate: PTHR1 gene mutation causes metaphyseal dysplasia.

Zone of terminal differentiation of the growth plate: RUNX2 gene mutation causes cleidocranial dysplasia

SKELETAL DYSPLASIAPREVALENCEThe prevalence of skeletal dysplasias (excluding limb amputations) is estimated at 2.4 per 10,000 births.In a large multicenter study found that 23% of patients with skeletal dysplasia were stillborn and 32% died within 1 week

The overall prevalence of skeletal dysplasias among perinatal deaths was 9.1 per 1000 cases

SKELETAL DYSPLASIADIAGNOSTICLong bones in all of the extremities should be measured. If limb shortening is present, the segments involved should be defined

Thorax. The chest circumference and cardiothoracic ratio should be measured at the level of the four chamber view of the heart

Hands and Feet should be evaluated to exclude the presence of a pre or postaxial polydactyly, syndactyly, clinodactyly, other deformities.

Foot length should be measured and any missing bones evaluated.

Skull. Head circumference and biparietal diameter should be measured. The shape, mineralization, and degree of ossification of the skull should be evaluated.

Cardiopulmonary disorders, such as dysgammaglobulinemia, familial dysautonomia, severe recurrent pneumonias with bronchiectasis or with intractable asthma and congenital heart defects, especially cyanotic forms Chromosomal disordersEndocrine disorders, such as pituitary skeletal dysplasia, growth hormone deficiency, Mauriac syndrome, and Shwachman syndromeInborn errors of metabolism, such as lysosomal storage disordersIntrauterine growth retardation, such as maternal insufficiency due to drugs, ethanol, infections including rubella, cytomegalic inclusion disease, syphilis, and toxoplasmosis; fetal insufficiency due to chromosomal disorders; and placental insufficiency Nutritional disorders due to inadequate energy intake, such as cleft palate, anorexia, deprivation, feeding problems, and severe malnutrition such as kwashiorkor or marasmus Primary growth disturbances, such as primordial skeletal dysplasia, Seckel syndrome, and Weill-Marchesani syndrome*

SKELETAL DYSPLASIADIAGNOSTICSpine should be carefully imaged to assess the relative total length and the presence of curvature to exclude scoliosis. Mineralization of vertebral bodies and neural arches should be evaluated

The shape of the pelvis can be important in certain dysplasias and dysostoses, such as limb-pelvic hypoplasial femoral hypoplasia, etc

SKELETAL DYSPLASIADIAGNOSTICDiagram illustrates a diagnostic algorithm for use in fetuses with suspected skeletal dyspla- sia and thoracic abnormalities. OI = osteogenesis imperfecta.

Cardiopulmonary disorders, such as dysgammaglobulinemia, familial dysautonomia, severe recurrent pneumonias with bronchiectasis or with intractable asthma and congenital heart defects, especially cyanotic forms Chromosomal disordersEndocrine disorders, such as pituitary skeletal dysplasia, growth hormone deficiency, Mauriac syndrome, and Shwachman syndromeInborn errors of metabolism, such as lysosomal storage disordersIntrauterine growth retardation, such as maternal insufficiency due to drugs, ethanol, infections including rubella, cytomegalic inclusion disease, syphilis, and toxoplasmosis; fetal insufficiency due to chromosomal disorders; and placental insufficiency Nutritional disorders due to inadequate energy intake, such as cleft palate, anorexia, deprivation, feeding problems, and severe malnutrition such as kwashiorkor or marasmus Primary growth disturbances, such as primordial skeletal dysplasia, Seckel syndrome, and Weill-Marchesani syndrome*

SKELETAL DYSPLASIADIAGNOSTICDiagram illustrates a diagnostic algorithm for use in fetuses with suspected skeletal dysplasia and skull abnormalities. OI = osteogenesis imperfecta.

Cardiopulmonary disorders, such as dysgammaglobulinemia, familial dysautonomia, severe recurrent pneumonias with bronchiectasis or with intractable asthma and congenital heart defects, especially cyanotic forms Chromosomal disordersEndocrine disorders, such as pituitary skeletal dysplasia, growth hormone deficiency, Mauriac syndrome, and Shwachman syndromeInborn errors of metabolism, such as lysosomal storage disordersIntrauterine growth retardation, such as maternal insufficiency due to drugs, ethanol, infections including rubella, cytomegalic inclusion disease, syphilis, and toxoplasmosis; fetal insufficiency due to chromosomal disorders; and placental insufficiency Nutritional disorders due to inadequate energy intake, such as cleft palate, anorexia, deprivation, feeding problems, and severe malnutrition such as kwashiorkor or marasmus Primary growth disturbances, such as primordial skeletal dysplasia, Seckel syndrome, and Weill-Marchesani syndrome*

SKELETAL DYSPLASIADIAGNOSTIC CONSIDERATIONSCardiopulmonary disorders, such as dysgammaglobulinemia, familial dysautonomia, severe recurrent pneumonias with bronchiectasisChromosomal disordersEndocrine disorders, such as pituitary skeletal dysplasia and growth hormone deficiencyInborn errors of metabolism, such as lysosomal storage disordersIntrauterine growth retardation, such as maternal insufficiency due to drugs, ethanol and infections including rubellaNutritional disorders due to inadequate energy intake, such as cleft palate, anorexia, etcPrimary growth disturbances, such as primordial skeletal dysplasia, Seckel syndrome and Weill-Marchesani syndrome

SKELETAL DYSPLASIAHISTOLOGIC FINDINGSCytoplasmic inclusions in resting chondrocytes reveal type I achondrogenesis, Kniest dysplasia, pseudoachondroplastic SED, type III short-rib polydactyly syndrome, and SED congenita. Large ballooned chondrocytes with clear cytoplasm and markedly deficient cartilaginous matrix reveal type II achondrogenesis.Resting cartilage with myxoid degeneration (Swiss cheese cartilage) may indicate Kniest dysplasia.

Histopathologic and electron microscopic examinations of chondro-osseous tissue may be helpful in delineating a particular skeletal dysplasia. Histologic studies of growth plates

SKELETAL DYSPLASIATREATMENT & MANAGEMENTPrenatal detection of skeletal dysplasias may influence the obstetric and perinatal treatment of affected infants.

MEDICAL CAREMedical care for individuals with skeletal dysplasia should be directed at preventing neurologic and orthopedic complications due to spinal cord compression, joint instability, and long bone deformity.

Administer neonatal resuscitation and ventilatory support.Monitoring height, weight, and head circumference of a child with skeletal dysplasia is important

Obstructive sleep apnea may be treated by adenotonsillectomy, weight reduction, continuous airway pressure by a nasal mask, and tracheostomy in extreme cases

SKELETAL DYSPLASIATREATMENT & MANAGEMENTSURGICAL CAREThoracolumbar kyphosis can be controlled with a Milwaukee brace fitted with kyphosis pads

Surgical intervention depends on the signs and symptoms of skeletal dysplasia as follows:Progressive kyphosis, which may lead to spinal cord compression and spastic paraparesis, is best treated by anterior and posterior fusion

Progressive scoliosis requires spinal fusion

one marrow transplantation may benefit patients with skeletal dysplasia associated with congenital immune deficiencies, etc

ACHONDROPLASIAAbnormal shape and size of skeletal dysplasia

ACHONDROPLASIAare a heterogeneous group of disorders characterized by intrinsic abnormalities in the growth and/or remodeling of cartilage and bone

These dysplasias affect the skull, spine, and extremities in varying degrees

They frequently cause a disproportionately short stature

Achondroplasia is the most common type of short-limb disproportionate dwarfism

ACHONDROPLASIAPREVALENCEAchondroplasia occurs in one in every 15,000 to one in 40,000 live births. The FGFR3 is the only gene known to be associated with achondroplasia. All people who have only a single copy of the normal FGFR3 gene and a single copy of the FGFR3 gene mutation have achondroplasia

ACHONDROPLASIAMORTALITY / MORBIDITYIn children younger than 4 years, death most commonly occurs due to brain stem compression, which causes sudden deathIn aged 5-24 years, central nervous system and respiratory abnormalities are the common causes of deathIn aged 25-54 years, cardiovascular problems are the most frequent causes of death

ACHONDROPLASIAPATHOPHYSIOLOGYThe primary defect found in patients with achondroplasia is abnormal endochondral ossification. Periosteal and intramembranous ossification is normal.

Impact on receptor

The mutations that cause achondroplasia act by exaggerating the negative regulatory functions of FGFR3 on endochondral ossification

to understand how this occurs, one must consider the impact of the mutation on receptor itself and that on the growing skeletonImpact on the growing skeleton

ACHONDROPLASIADIAGNOSTICSkeletal X-rays demonstrate rhizomelia, generalized metaphyseal irregularities, narrowing of the interpediculate

Diagnosis is based on the presence of characteristic clinical and radiological findings. Molecular genetic testing can confirm a diagnosis by the presence of a FGFR3 mutation.

Differential diagnoses include hypochondroplasia, thanatophoric dwarfism (types I and II), and SADDAN

In high risk pregnancies, or in those where achondroplasia is suspected after an ultrasound

ACHONDROPLASIAOBSTETRICAL MANAGEMENTTreatment of ear infections and serous otitis media, along with assessment of any hearing problems is needed

Obstetrical management is multidisciplinary and anticipatory care is essentialSpeech therapy can be offered if concerns arise

Treatment of obstructed sleep apnea may include adenotonsillectomy, weight loss, and/or continuous positive airway pressure

Weight gain should be monitored in childhood to avoid later complications, activities. And social & physchological support

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METABOLIC BONE DWARFISM

METABOLIC BONE DWARFISMMetabolism is the set of chemical reactions that turn an ingested substance into something the body can use such as a basic nutrient or a source of energyIn the case of some diseases, flaws may occur during metabolism

When the metabolism of calcium, phosphorous, carbohydrates, and fats is flawed, bone growth and structure may be affected.

MUCOPOLYSACCHARIDOSESAre a heterogeneous group of inherited metabolic disorders caused by enzyme deficiencies that lead to progressive lysosomal accumulation of glycosaminoglycans (GAGs).

The seven major types of MPS are categorized on the basis of the specific enzyme deficiency present, the major clinical manifestations or both

Early in the disease course and in those with milder forms of disease patients with MPS may first seek medical attention because of musculoskeletal complaints.

MUCOPOLYSACCHARIDOSESHurler syndrome (MPS IH)Hurler-Scheie syndrome (MPS I-H/S)Scheie syndrome (MPS IS)Hunter syndrome (MPS II)Sanfilippo syndrome (MPS III)Morquio syndrome (MP IV)Maroteaux-Lamy syndrome (MPS VI)Sly syndrome (MPS VII)

MUCOPOLYSACCHARIDOSESPREVALENCEThe prevalence of all types of MPS is 1 case in 16,000-30,000 births. MPS III accounts for 80% of cases. These syndromes are found in persons of all ethnic groups, but prevalence is increased in Israeli Jews and French Canadians.

MUCOPOLYSACCHARIDOSESMORTALITY/MORBIDITYThese disease processes have significant effects on the growth and development of the musculoskeletal system. The type and extent of organ system involvement are variable depending on the subset of the diseaseMost of these patients have shortened life spans and some of them die in infancy

These syndromes are found in all ethnic groups.RaceMPS features mostly present in the first few months of life. However, Morquio syndrome usually presents in children aged 2-4 years, and MPS IS and MPS VI can present late in childhoodAgeSexAll mucopolysaccharidoses are inherited as autosomal recessive disorders with the exception of Hunter syndrome (MPS II), which is inherited as sex-linked recessive condition.

MUCOPOLYSACCHARIDOSESPATHOPHYSIOLOGYPathophysiology of muccopolysaccharidose (MPS)

MUCOPOLYSACCHARIDOSESPATHOPHYSIOLOGY

Mucopolysaccharidosis Type Syndrome NameDeficiencyMPS type I-HHurler syndromeAlpha-L-iduronidaseMPS type I-SScheie syndromeAlpha-L-iduronidaseMPS type I-H/SHurler-Scheie syndromeAlpha-L-iduronidaseMPS type IIHunter syndromeL-sulfoiduronate sulfataseMPS type IIISanfilippo syndrome type A, B, C, DHeparan sulfate sulfamidase, N -acetyl-alpha-D-glucosaminidase, alpha-glucosamide N -acetyltransferaseMPS type IV-AMorquio syndrome, classic formN -acetylgalactosamine-6-sulfatase (gal-6-sulfatase)MPS type VIMaroteaux-Lamy syndrome, mild formN -acetylgalactosamine-4-sulfatase (arylsulfatase B)MPS type VIISly syndromeBeta-glucuronidase

MUCOPOLYSACCHARIDOSESCLINICAL MANIFESTATIONSBoth of Disproportionate Short Stature (DSS) and Proportionate Short Stature (PSS) is a common feature in all types of MPSAxial growth is usually affected more than appendicular growth resulting in disproportionately short stature.Final height in affected patients is frequently 3-6 SD below the mean height for age and gender

The accumulation of partially degraded GAGs in the lysosomes of connective tissue cells and chondrocytes is thought to be responsible for most of the musculoskeletal manifestations seen in the different types of MPS

MUCOPOLYSACCHARIDOSESCLINICAL MANIFESTATIONSJoint stiffness and contractures can be found in all types of MPS, except for MPS IV (Morquio syndrome).Joint stiffness and contracturesJoint hypermobility is seen in the majority of patients with Morquio syndrome (MPS IV)Joint hypermobilityDysostosis multiplex is the term used to describe the constellation of radiographic changes characteristically seen in MPSDysostosis multiplex

MUCOPOLYSACCHARIDOSESCLINICAL MANIFESTATIONSPeriarticular osteopenia, joint space narrowing of the IP joints and intercarpal joints, erosive changes of the second and third PIP joints bilaterally

MUCOPOLYSACCHARIDOSESDIAGNOSTICThe recognition that almost all MPS patients present mucopolysachariduria, which may be easily identified by qualitative and quantitative methodsFinal diagnosis is based on the identification of the specific enzyme deficiencyThis could be achieved by analysis using cultured fibroblasts, plasma or peripheral blood leukocytesuse of dried blood spots (DBS) as enzyme source and confirmed through leucocyte analysis

The identification of the gene defect is not required for diagnosis but can be helpful for phenotype prediction and for the identification of carriers

flow-chart for the diagnosis of MPS using blood and urine samples

MUCOPOLYSACCHARIDOSESPRENATAL DIAGNOSTICPrenatal diagnosis for MPS was performed even before the enzyme deficiencies were identified, as increased GAGs could be detected in the amniotic fluid of affected fetusesaccurate prenatal diagnosis became available once the enzyme defects were known, and amniotic fluid cells, chorionic villi or cord blood could be used as a source for measuring enzyme activity

HURLER SYNDROME

HURLER SYNDROMEPATHOPHYSIOLOGY

Hurler syndrome is characterized by a near total absence of enzyme -L-iduronidase activity

HURLER SYNDROMEPREVALENCEBirth prevalence of MPS I. The horizontal represents the overall birth prevalence (1.07/100,000 live births) for MPS I.

HURLER SYNDROMECLINICAL DISEASE MANIFESTATIONSClinical manifestations of mucopolysaccharidosis type I (MPS I) show a chronic multisystemic and progressive courseSymptoms across the types include facial dysmorphism, corneal clouding, hepatomegaly, valvular heart disease, obstructive airway disease, developmental delay, hearing loss, skeletal deformities, and joint stiffness.For patients with the more severe form of the disease, the most typical symptoms occur early in life. typically have numerous progressively debilitating symptoms, including mental retardationTheir lifespan is less than 10 years

Individuals with less-severe disease can have some of the same physical symptoms

HURLER SYNDROMECLINICAL DISEASE MANIFESTATIONSFacial dysmorphism or coarsened facial featuresCorneal cloudingVisceral involvementSkeletal involvementJoint stiffnessCardiopulmonaryDevelopment delay

HURLER SYNDROMEDIAGNOSTICThe earliest diagnostic tests for the MPS disorders were based on the urinary excretion of glycosaminoglycans

Biochemical DiagnosisMolecular diagnosis of Hurler syndrome is difficult because of the genetic heterogeneity in MPS I

Molecular Diagnosis

HURLER SYNDROMECLINICAL MANAGEMENTAnesthesia

Plasma Infusion/Fibroblast Transplantation

Bone Marrow Transplantation (BMT)

Enzyme Replacement

Cord Blood Transplants

HUNTER SYNDROME

HUNTER SYNDROMEHunter syndrome is an X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase (I2S)The clinical phenotype of MPS II is characterised by progressive pathological lysosomal storage of GAGs in nearly all cell types, tissues and organs

HUNTER SYNDROMEAppearance of a child with mucopolysaccharidosis type II (Hunter syndrome). (a) 6 years of age and (b) 12 years of age, illustrating the typical clinical phenotype at the more severe end of the disease spectrum

HUNTER SYNDROMEPATHOPHYSIOLOGY

HUNTER SYNDROMEPREVALENCEIncidence of MPS II is 1.3 per 100,000 male live birthsThe clinical phenotype of MPS II is characterised by progressive pathological lysosomal storage of GAGs in nearly all cell types, tissues and organsData from The Netherlands and Germany

HUNTER SYNDROMECLINICAL SPECTRUMReported age at onset and prevalence of clinical features in 82 patients with mucopolysaccharidosis type II (Hunter syndrome) enrolled in HOS, the Hunter Outcome Survey

HUNTER SYNDROMEMORTALITY/MORBIDITYMortality by age of patients with mucopolysaccharidosis type II (Hunter syndrome) in the UKDeath from a combination of neurological deterioration and cardiorespiratory failure usually occurs in the mid-teenage years

HUNTER SYNDROMEPHYSICAL APPEARANCEThe typical patient with attenuated MPS II is short with some change of facial features.

Significant arthropathy and connective tissue involvement lead to joint contractures

Combination of hepatomegaly and lax abdominal muscles leads to abdominal prominence.

Facial and body hypertrichosis is often seen and the scalp hair becomes coarse, straight and thatch-like

HUNTER SYNDROMEDIAGNOSTICBiochemical diagnosisAssessing urinary GAGs (heparan and dermatan sulphates) is the usual first screening test for MPS Iquantitative (measurement of total urinary uronic acid) qualitative (GAG electrophoresis)

Prenatal diagnosisPrenatal testing is available for foetuses at risk of MPS IICarrier testingPrevious methods of carrier detection based on an I2S assay in either plasma or hair roots

HUNTER SYNDROMECLINICAL MANAGEMENTAnaesthetic All patients with MPS II present major anaesthetic risks, and death can result if appropriate precautions are not takenEnzyme replacement therapyRecombinant I2S has recently been licensed for treatment of patients with MPS II in the United States, European Union and SwitzerlandHome therapyHaematopoietic stem cell therapy (HSCT)

SAN FILIPPO SYNDROME

SAN FILIPPO SYNDROMEAn autosomal recessive lysosomal storage disorder caused by a deficiency of one of the four enzymes involved in the degradation of the glycosaminoglycan heparan sulfate

Sannfilippo syndromeChromosome GeneEnzymetype A17q25.3SGSHN-sulfoglucosamine sulfohydrolasetype B17q21.2NAGLUN-acetyl-alpha-D-glucosaminidase type C8p11.21HGSNATacetyl-CoA, alpha-glucosaminide-N-acetyltransferasetype D12q14.3GNSN-acetylglucosamine-6-sulfatase

SAN FILIPPO SYNDROMEPATHOPHYSIOLOGY

SAN FILIPPO SYNDROMEPREVALENCEThe estimated incidence of MPS III (all four types combined) is 1 in 70,000 births

SAN FILIPPO SYNDROMECLINICAL DISEASE MANIFESTATIONSNeurocognitive manifestationspatients with MPS III typically present with mainly cognitive and neurological signs and symptomsSomatic manifestationsSomatic symptoms are heterogeneous in the MPS III population and can be much more subtle than those seen in the other MPS disorders

SAN FILIPPO SYNDROMECLINICAL DISEASE MANIFESTATIONSPatients with MPS III often have only mildly coarse facial features

SAN FILIPPO SYNDROMEDIAGNOSISBiochemical testinguGag excreationEnzyme activity assaysGenetic testing

SAN FILIPPO SYNDROMECLINICAL MANAGEMENTPatients with a confirmed diagnosis of MPS III should be promptly referred to a metabolic disease specialistOnce the referral has been made, the paediatrician maintains a key role in overseeing the management of these patients child may need to be seen by multiple specialistsCardiologyNeurodevelopmentOphthalmologyOrthopaedicsOtorhinolaryngologypsychiatry PulmonologyPhysiotherapy (additional as support service)

MORQUIO SYNDROME

MORQUIO SYNDROME

Key clinical features include short stature, skeletal dysplasia, dental anomalies, and corneal cloudingMucopolysaccharidosis type IV is an autosomal recessive lysosomal storage disease characterized by intracellular accumulation of keratin sulfate and chondroitin-6-sulfateIntelligence is normal and there is no direct central nervous system involvement

MORQUIO SYNDROMEPATHOPHYSIOLOGY

MORQUIO SYNDROMEPREVALENCEThe incidence is unknown but is estimated to be between 1 in 75 000 population in Northern Ireland to 1 in 200 000 population in British Columbia The male-to-female ratio is 1:1, and this is supported by the demographics of the cohort in a natural history study

MORQUIO SYNDROMECLINICAL DISEASE MANIFESTATIONSfacial appearance that may include an enlarged head, broad mouth, prominent cheekbones, an unusually small nose, widely spaced and thinly enameled teeth, and widely separated eyes with subtle corneal cloudingThe liver and spleen may be mildly enlargedThe elbows, wrists, hips, knees and other large joints are abnormally flexible, causing overall instability

MORQUIO SYNDROMECLINICAL DISEASE MANIFESTATIONSSigns and symptoms that should generate clinical suspicion of MPS IVA

Skeletal abnormalitiesNon-skeletal abnormalitiesShort statureRespiratory compromiseaAbnormal gaitEndurance limitationsGenu valgumRecurrent respiratory infectionsSpinal abnormalitiesSleep apneaOdontoid hypoplasiaSnoringCervical instabilityCardiac valve abnormalitiesKyphosis/GibbusMuscular weakness

MORQUIO SYNDROMECLINICAL DISEASE MANIFESTATIONSSigns and symptoms that should generate clinical suspicion of MPS IVA

Skeletal abnormalitiesNon-skeletal abnormalitiesScoliosisVisual impairmentChest abnormalitiesCorneal cloudingPectus carinatumAstigmatismPectus excavatumHearing lossaJoint abnormalitiesConductiveJoint hypermobilitySensorineuralJoint painDental abnormalities and oral health challengesa

Algorithm for the diagnosis of Morquio Syndrome

MORQUIO SYNDROMECLINICAL MANAGEMENTAnesthetic management

THANK YOUFITRI APRILLIA, 2015

Cardiopulmonary disorders, such as dysgammaglobulinemia, familial dysautonomia, severe recurrent pneumonias with bronchiectasis or with intractable asthma and congenital heart defects, especially cyanotic forms Chromosomal disordersEndocrine disorders, such as pituitary skeletal dysplasia, growth hormone deficiency, Mauriac syndrome, and Shwachman syndromeInborn errors of metabolism, such as lysosomal storage disordersIntrauterine growth retardation, such as maternal insufficiency due to drugs, ethanol, infections including rubella, cytomegalic inclusion disease, syphilis, and toxoplasmosis; fetal insufficiency due to chromosomal disorders; and placental insufficiency Nutritional disorders due to inadequate energy intake, such as cleft palate, anorexia, deprivation, feeding problems, and severe malnutrition such as kwashiorkor or marasmus Primary growth disturbances, such as primordial skeletal dysplasia, Seckel syndrome, and Weill-Marchesani syndrome*Cardiopulmonary disorders, such as dysgammaglobulinemia, familial dysautonomia, severe recurrent pneumonias with bronchiectasis or with intractable asthma and congenital heart defects, especially cyanotic forms Chromosomal disordersEndocrine disorders, such as pituitary skeletal dysplasia, growth hormone deficiency, Mauriac syndrome, and Shwachman syndromeInborn errors of metabolism, such as lysosomal storage disordersIntrauterine growth retardation, such as maternal insufficiency due to drugs, ethanol, infections including rubella, cytomegalic inclusion disease, syphilis, and toxoplasmosis; fetal insufficiency due to chromosomal disorders; and placental insufficiency Nutritional disorders due to inadequate energy intake, such as cleft palate, anorexia, deprivation, feeding problems, and severe malnutrition such as kwashiorkor or marasmus Primary growth disturbances, such as primordial skeletal dysplasia, Seckel syndrome, and Weill-Marchesani syndrome*Cardiopulmonary disorders, such as dysgammaglobulinemia, familial dysautonomia, severe recurrent pneumonias with bronchiectasis or with intractable asthma and congenital heart defects, especially cyanotic forms Chromosomal disordersEndocrine disorders, such as pituitary skeletal dysplasia, growth hormone deficiency, Mauriac syndrome, and Shwachman syndromeInborn errors of metabolism, such as lysosomal storage disordersIntrauterine growth retardation, such as maternal insufficiency due to drugs, ethanol, infections including rubella, cytomegalic inclusion disease, syphilis, and toxoplasmosis; fetal insufficiency due to chromosomal disorders; and placental insufficiency Nutritional disorders due to inadequate energy intake, such as cleft palate, anorexia, deprivation, feeding problems, and severe malnutrition such as kwashiorkor or marasmus Primary growth disturbances, such as primordial skeletal dysplasia, Seckel syndrome, and Weill-Marchesani syndrome*

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