Osteogenesis Imperfecta: Types, Causes, and Manifestations

Osteogenesis Imperfecta

• Autosomal dominant inherited condition characterized by bone fragility
• Defect in Type I collagen production
• Type I collagen is a major extracellular protein, key to dermis, connective tissue of organ capsules, and vascular and GI adventitia; the only collagen type in bone.
• Type I collagen is normally composed of two a1 chains and one a2 chain encoded by COL1A1 and COL1A2, which form a triple helix
• COL1A1 and COL1A2 encode type I collagen subunits
• The classical group includes 90% of cases, resulting from a COL1A1 or COL1A2 gene variant.
• Types I-IV are all autosomal dominant
• Overarching molecular pathophysiology for OI: 90% of cases d/t variant leading to defect in type I collagen formation
• Greater incidence in females
• Various pathogenic variants and genes subject to alteration result in a wide spectrum of clinical phenotypes.
• Clinical manifestations include brittle bones, with less severe forms manifesting in childhood/adolescence.
• The blue sclera results from tissue thickening and type 1 collagen deposition.
• Other clinical indications include Long bone fractures with minor trauma
• Other clinical indications Kyphoscoliosis which is restrictive lung disease
• Bow Legs are are other clinical indications
• Others include Gradual onset of otosclerosis and deafness and Osteopenia
• Also impaired platelet function which leads to bleeding tendency
• Increased serum thyroxine concentration d/t increased oxygen consumption occurs in 50% of patients
• Treatment includes bisphosphonates to strengthen bones focusing on pain and limiting fractures

Phenylketonuria (PKU)

• Primary defect is hyperphenylalaninemia
• Elevated circulating blood levels of phenylalanine > 1.2 mmol/L
• Elevated phenylpyruvate and phenylacetate in urine when phenylalanine > 1.2 mmol/L
• Deficiency in phenylalanine hydroxylase (responsible for catabolism of phenylalanine to tyrosine)
• d/t defects in BH4
• Decreased levels of tyrosine, melanin catecholamines, ketone bodies, gluconeogenesis, and protein synthesis
• Clinical manifestations are not caused by absence of tyrosine (d/t dietary supplementation) but rather by the accumulation of phenylalanine
• Protein-rich foods and aspartame can lead to elevated phenylalanine levels
• Elevated phenylalanine levels cause alterations in protein and energy production, as well as neurotransmitter homeostasis in the developing brain (d/t lack of amino acid BBB transport)
• Clinical manifestations: include Post-natal growth restriction, Moderate-severe intellectual disability (decreased executive), Recurrent seizures, and Hypopigmentation
• Mothers with PKU expose fetus to fetal hyperphenylalaninemia, Microencephaly, congenital heart disease, and developmental delays
• Treatment involves dietary restriction of phenylalanine to levels under 1 mmol/L and Somatic gene therapy
• Includes Dietary supplementation of BH4, dopa, and 5-hydroxytryptophan

Fragile X-associated mental retardation syndrome

• Genetic disorder causes intellectual disability and cognitive impairment
• Characteristic features: Long and narrow face, large ears, prominent forehead, and low muscle tone
• Fragile X genes are located on are on X chromosome; under microscope appears fragile at mutation site
• Amplification of the CGGn repeat at the fraXq27.3 site affects both methylation and expression of the FMR1 gene
• This affects regulations for translation for mRNA molecules aiding in brain and tissue development
• Methylated cytosine caused chromatin to be condensed→ regions of FMR1 cannot be bound by transcription factors→ deactivates promotor of FMR1= decreased FMRP
• Affects males more than females; never transmitted from father to son (only from mother)
• Clinical manifestations:
• In affected males Developmental delay (present by 1-2 years) Family history of intellectual disability maternally related
• Physical characteristics in males include, Large testes and ears as well as Prominent forehead and mandible, and Long face, relative macrocephaly
• Affected females: milder intellectual disability; reduced symptoms and Small joint hyperextensibility and Mild hypotonia leads to delayed motor development and speech

Marfan Syndrome

• It is an Autosomal dominant connective tissue disorder that causes morbidity related to cardiopulmonary issues; almost all premature deaths in this population
• Connective tissue defect results in aortic dilation, dissection, rupture, and/or prolapse valves
• Mitral regurgitation can be secondary to mitral valve prolapse
• Patho: Connective tissue disorder secondary to defects in glycoprotein fibrillin-1
• Fibrillin-1 gene (FBN1) located on chromosome 15
• FBN1 encodes Structural extracellular matrix protein for Regulation and regulation and tissue growth
• It removes/sequesters TGF-B (transforming growth factor beta) and TGF=B stimulates tissue growth
• Decrease/dysfunction of fibrillin-1 = fewer functioning microfibrils in extracellular matrix = compromised tissue integrity and elasticity
• Clinical manifestations include "Abe Lincoln appearance" which means the patients are tall, long tubular bones with a High arched palate which leads to a difficult intubation
• Other Clinical manifestations include, Pectus excavatum which causes a restrictive lung disease w/ early obstructive disease
• Patients typically display Joint laxity which causes a High risk for spontaneous pneumothorax
• Signs of Joint Laxity include Acute dyspnea, pleuritic chest pain, that is usually If unilateral, pain is greater on ipsilateral side and Decreased chest excursion on affected side, diminished breath sounds, hyperresonant percussion
• A late sign is Tracheal deviation away from affected side and hemodynamic compromise
• The syndrome also leads to ocular changes such Lens dislocation, nearsightedness, and retinal detachment (more than half have this)
• Anesthesia considerations include assessing cardiopulmonary status and Tight control of BP
• Cardiopulmonary status is needed because BBB can commonly be found
• Beta blockade often needed lifelong because of d/t dilated thoracic aorta; and sustainment of increased BP
• Also Increased transmural pressure = risk of dissection
• increased risk of pneumothorax, TMJ dislocation,

Down Syndrome (Trisomy 21)

• It is most common chromosomal abnormality; Results of an extra chromosome 21 and also, the Incidence parallels advanced maternal age
• The common cause is meiotic nondisjunction and Robertsonian Translocation can also occur
• Clinical manifestations include Intellectual disability which is present (present 3-6 months of age) and Increased infections and risk of acute anemia
• Other Features include Premature onset of Alzheimer's, Epicanthal folds, Small ears Transverse palmar creases,hypotonia, Congenital heart disease (50%) and ASD, AV malformations, VSD, and Brachycephaly
• Considerations: increased risk for difficult airway Short neck, Micrognathia, tonsillar adenoidal hypertrophy, redundant soft tissue, Macroglossia predisposed to upper airway obstruction
• At high risk for postintubation croup d/t smaller subglottic airway
• Small airway insults can lead to clinically significant subglottic stenosis and Smaller ETT may be needed than normal sizing
• Specific considerations related to congenital heart defects and hypotonia with joint laxity both increased risk for musculoskeletal injury and atlantoaxial instability

Ehlers-Danlos Syndrome

• It is Hereditary connective tissue disorders resulting from abnormal procollagen and collage production
• Vascular type = most at risk for increased mortality and risk for rupturing of large blood vessels, bowel, uterus
• All forms are single gene disorders and the Molecular basis of the three most common variants includes:
• Mutation of COL3A1 gene = deficient synthesis of type III collagen and this is Inherited autosomal dominant disorder
• Lysyl hydroxylase deficiency= Deficient lysyl hydroxylase enzyme = decreased hydroxylation of lysyl residues in type I and type III collage
• Clinical All forms display joint hypermobility = predisposed to dislocation, skin fragility/hyperplasticity, musculoskeletal pain, susceptible to development of OA
• Gl tract, uterus, and vascular contain a large amount of type III collagen = risk for rupture and display, Tracheal dilation Cardiac conduction abnormalities and mitral regurgitation
• Clinical manifestations: All forms = joint hypermobility, skin fragility/hyperplasticity, musculoskeletal pain, and susceptible to development of OA
• Considerations: At risk for excessive bleeding from avoid poking holes from IM injections, regional anesthesia and Increased incidence of pneumothorax, that requires a ventilation
• Maintain low airway pressures during mechanical ventilation

Klinifelter Syndomre

• Cytogenetic disorder involving sex chromosomes and Male hypogonadism develops when there are at least two X chromosomes and one Y chromosome
• The most effected patients= 47, XXY karyotype, and results from nondisjunction of chromosomes during meiosis
• Contributing factors often involve Advanced maternal age and History of irradiation in either parent
• Clinical manifestations: include Distinct body habitus = elongated body, reduced facial and body hair, Gynecomastia, Hypogonadism decreased testosterone with increased libido among other factors
• It also increases risk for Degree of mental impairment, breast cancer, autoimmune diseases, and extragonadal germ cell tumors

Turner Syndrome

• Hypogonadism in phenotypical females of complete monosomy short arm of the sex chromosome

• Most patients are missing an entire X chromosome and 45,X Karyotype is the most prevelant

• It occurs in Incidence: 1:3,000 female births and the Pathogenesis, is still yet completely understood

• Potential karyotypes: nondisjunction of sex chromosomes during meiosis 45,X karyotype which is the most common;missing the entire x chromosome mosaicism in which some cells have the x chromosome and the error occurred after conception missing the short arm

• common cardiac comorbidities: COA and bicuspid aortic valve (most common cause of death in childhood for this population)

• see picture for typical features

   failure to develop secondary sex characteristics
  

• normal mental status

• hypothyroidism

• accelerated loss of oocytes = ovaries become atrophic fibrous strands, devoid of ova and follicles

• considerations:

• difficult intubation d/t high arched palate, short neck

(mandibular and maxillary hypoplasia)

short neck may lead to a higher level of tracheal bifurcation with a shorter trachae
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  Considerations for Osteogenesis Imperfecta:

• existing orthopedic deformities and potential for increased injury

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• decreased range of motion of c-spine d/t bone remodeling minimal manipulation for endotracheal intubation

cervical and mandibular fractures Increased risk of dental injury Succinylcholine fasciculations can lead to fractures potentially dangerous Regional anesthesia is safe

• be technically kyphoscoliosis assess platelet function! Might have mild hyperthermia unique laboratory findings for PKU blood levels of phenylalanine are greater than

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