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Gastrointestinal (Congenital Anomalies (Diaphragmatic Hernia 1 in 3000…

- - - - Esophageal Atresia +/- Fistula
        
        common cause of neonatal regurgitation and aspiration pneumonia
        
        Can be isolated
        
        Can be part of VATER/VACTERL
        
        Can be syndromic
        
        23 disorders
        
        VACTERL
        V - vertebral defects
        A - anal atresia
        C - cardiac malformations
        T - tracheoesophageal fistula with
        E - esophageal atresia
        R - radial or renal dysplasia
        L - Limb abnormalities
        
        You need 3+ to arrive at a dx
        
        VACTERL-H (with hydrocephalus): PTEN 1 case
        
        VACTERL +/- H X-linked: ZIC3
        
        Fanconi Anemia
        
        Feingold syndrome
        
        Microcephaly
        
        Triangular face
        
        Craniofacial features
        
        EA, TEF (common in Feingold), Duodenal atresia
        
        Annular pancreas (the second part of the duodenum is surrounded by a ring of pancreatic tissue continuous with the head of the pancreas)
        
        Asplenia (absence of normal spleen function)
        
        Supernumerary spleen
        
        Digit abnormalities
        
        Intellectual disability
        
        MYCN gene OR
        
        Hemizygous deletion of the MIR17HG gene
      - Duodenal Atresia
        
        Obstruction to passage of food through duodenum
        
        Associated with Down syndrome
        
        But can be isolated
        
        Double bubble prenatal Ultrasound
      - Anal Atresia
        
        1 in 5000 births
        
        greater than 50% are syndromic
        
        VACTERL
        
        Cat-eye syndrome
        
        Townes-Brock
        
        Cat-Eye syndrome
        
        Inverted, small, supernumerary chromosome, frequently bisatelited
        
        inverted dup(22)(q11)
        
        4 copies of 22
        
        often mosaic
        
        coloboma of the iris
        
        anal atresia with fistula
        
        cardiac, renal malformations
        
        downslanting palpebral fissures
        
        preauricular tags/pits
        
        normal or near normal development
        
        Townes-Brock syndrome
        
        Hand and foot anomalies
        
        triphalangeal thumbs
        
        when the thumb has 2 knuckles, it looks like a finger
        
        Sensorineural deafness
        
        Malformed auricles "lop or satyr" ears
        
        folding of superior helix
        
        preauricular tags/pits
        
        Anal atresia
        
        Cardiac and renal defects
        
        SALL1 tx factor gene
        
        "REAR" syndrome (renal ear anal radial)
  - - - Risk of Pyloric Stenosis
        
        Highest frequency in male relatives of female affecteds (17%)
        
        Lowest is female 1st degree relatives of male affecteds (2-3%)
        
        For a male to get it, there is less genetic load than there is for a female
        For a male to get it, all you need is a predisposition to reach the threshold
        Females need a higher genetic load to reach that threshold
  - - - Genetics
        
        All 4 genes (CdLS1-4) encode components of the cohesin complex, resulting in defective DNA repair
        
        For AD forms, < 1% have affected parent
        
        CdLS1:
        
        NIPBL 60% of cases
        (2% intragenic deletions)
        
        CdLS2:
        
        SMC1A 5% of cases
        
        X-linked
        
        no limb defects, but have short hands; more palatal defects
        
        escapes x-inactivation, females less affected than NIPBL females; males more severe than females
        
        CdLS3:
        
        SMC3
        
        milder
        
        no limb abnormalities
        
        no major malformations
        
        CdLS4:
        
        RAD21 < 1% of cases
        
        missense, whole gene deletions
        
        milder phenotype
        
        CdLS5
        
        HDAC8 4%
        
        x-linked, males typical CdLS features
  - - - Pathophysiology
        
        failure of neural crest-derived ganglion cells to colonize the entire gut
        
        These cells derive from the vagal neural crest, from hindbrain during neurulation
        
        Normal migration: cranial to caudal progression, rectum last
        
        Genetics
        
        Genetic heterogeneity
        -12% are due to chromosome abnormalities
        
        Down syndrome (no known HSCR gene on 21,? etiology)
        
        Chromosome deletions
        
        Evaluation
        
        18% at least one other anomaly, syndromic or unknown
        
        careful PE and fmhx
        
        labs
        
        monogenic syndromic: specific gene
        
        multiple anomalies, not identifiable: karyotype
        
        nonsyndromic monogenic: hirschprung panels available (10 genes); incomplete penetrance
    - - Syndromic Hirschsprung
        
        Mowat-Wilson syndrome 62-70%, ZFHX1B
        
        autosomal dominant
        
        intellectual disability, macrocephaly, CHD, ACC, epilepsy, short stature, dysmorphic features
        
        Goldberg-Shprintzen syndrome
        
        autosomal recessive (different than shprintzen-goldberg)
        
        similar to Mowat-Wilson but with CLP and coloboma
        
        Intestinal neuronal dysplasia, type B ~20%
        
        abnormal intestinal innervation with giant ganglia
        
        MEN2: RET gene
        
        autosomal dominant
        
        MEN2A) medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism
        
        MEN2B) medullary thyroid carcinoma, pheochromocytoma, mucosal and intestinal neuromas, skeletal abnormalities, corneal changes
        
        Waardenburg type 4
        
        generalized neurocristopathy
        
        pigmenatry abnormalities
        
        deafness
        
        autosomal recessive: EDNRB, EDN3
        
        autosomal dominant: SOX10
        
        L1 syndrome
        
        L1CAM,XLR
        
        intellectual disability, hydrocephalus, ACC, adducted thumbs
        
        NF1
        
        SLO
        
        Nonsyndromic Hirschprung Disease
        at least 6 genes
        
        genes for RET and its ligands
        
        RET: 17-38% short segment; 70-80% long segment; Autosomal dominant
        
        GDNF <1%
- - - - Penetrance Effects
        
        males: symptoms between 40-60 years
        
        hepatic fibrosis or cirrhosis rare (< 40)
        
        Females: after menopause
        
        Penetrance issues
        
        C282Y/H63D men showed 0.5-2.2% Fe overload
        C282Y Hz 1.6% of men
        H63D/H63D 1.9% of men
        C282Y/265C and H63D/265C rare and low risk
        
        Population Screening
        
        DNA testing
        
        unclear predictive value of a positive test
        
        Hematological testing
        
        Fe and transferrin saturation is the most sensitive screen
  - - - CNS findings
        
        cerebral atrophy
        
        hypodense areas in the midbrain, basal ganglia, thalamus, parietal white matter
        
        high signal in the thalami, putamen dentate nuclei, brainstem on T2 MRI
        
        Treatment
        
        copper chelating agents
        
        antioxidants
        
        restriction of food high in copper
        
        liver transplantation
        
        tetrathiomolybdate