With improvements in medical care, children with genetic diseases now live longer.
Transition of care of pediatric patients with chronic diseases to adult providers presents challenges, especially in the care of pediatric genetic diseases.
Adult patients with monogenic diseases diagnosed in childhood require an interdisciplinary approach to medical care.
Medical management of other adult-onset conditions not related to the primary diagnosis must be addressed.
The astute physician must sometimes differentiate between medical issues related to the primary genetic diagnosis and other nonrelated pathologic conditions.
Although the majority of conditions seen in adult medicine are multifactorial in nature, many monogenic disorders are becoming more frequent in adults due to improvements in health care, leading to longer survival of affected children.
There are two general scenarios where an adult physician may see a patient with a childhood genetic disorder:
When the patient is diagnosed in childhood and requires continuing care into adulthood (eg, Down syndrome).
When a new patient presents whose syndrome was not diagnosed in childhood.
Table 178-1 is a survey of genetic conditions that present in childhood and may continue into adulthood. This table is in no way intended to be exhaustive, but rather, gives an overview of the various monogenic and chromosomal disorders that may present to the adult physician. Further details of these conditions can be found in Online Mendelian Inheritance in Man (OMIM; proxy.library.upenn.edu:2084/omim/).
|OMIM # (Reference)||Heredity||Genes Involved||Disease Mechanism||Clinical Details||Management||Genetic Testing (Detection)|
Lack of protein product leads to increased dsDNA breaks and lack of coordination of cell cycle
Progressive cerebellar ataxia, conjunctival telangiectasias, immunodeficiency, increased risk of leukemia, and lymphoma. Death by 3rd decade.
IVIG for immunodeficiency, avoid radiation, supportive therapy
Mutation analysis (>95%)
Duchenne (DMD) and Becker (BMD) muscular dystrophy
Dystrophin binds muscle membrane proteins.
DMD: lack of dystrophin
BMD: abnormal quality or quantity of dystrophin
DMD: onset <5 y with proximal muscle weakness, calf hypertrophy, DCM, wheelchair 2nd decade, vent dependent/death 3rd decade
BMD: later-onset myopathy, DCM may occur in isolation, + wheelchair 2nd decade, death 5th-6th decade
Supportive therapy, steroids may prolong walking 2-3 y
Gene deletion: DMD (65%), BMD (85%) Gene duplication: DMD (6%) Mutations: DMD (30%)
X-linked triplet repeat
Full mutation: >200 CGG repeats silences gene by methylation
Premutation: 59-200 CGG repeats
Full mutation: Males–DD, MR, PDD spectrum, characteristic facies, macroorchidism at puberty Females–milder phenotype
Premutation: Males– tremor ataxia syndrome >50 y Females–premature ovarian failure
Supportive therapy, no treatment for tremor ataxia syndrome and premature ovarian failure
Targeted mutation analysis (>99%)
AR triplet repeat
Disease causing: 66-1700 GAA triplet repeats form stable DNA structure that inhibits transcription
Progressive degeneration of dorsal root ganglia and corticospinal and spinocerebellar tracts, optic nerve atrophy, hypertrophic cardiomyopathy, diabetes. Wheelchair bound in 15-20 years after first symptoms, death in early adulthood usually due to hypertrophic cardiomyopathy.
Targeted mutation analysis (98%)
Loss of function mutations (>500) disables ras GTPase control of cellular proliferation
Café-au-lait spots, neurofibromas (including plexiform), optic gliomas, Lisch nodules, bone malformations. Clinical diagnostic criteria
Surgery for bone malformations and neurofibromas. Risk of malignant transformation of neurofibromas.
Mutation analysis of gDNA and mRNA (90%)
Spinal cerebellar ataxias
~30 distinct clinical entities in OMIM
>25 loci identified
Multiple mechanisms including CAG repeat expansions, mutations, and deletions
Progressive gait ataxia, poor coordination of hands, speech, and eye movements, cerebellar atrophy
Ataxia panels available
Altered tumor suppressor function
Hypomelanotic macules, facial angiofibroma, Shagreen patch, ungual fibroma, subependymal nodules, cortical tubers, giant cell astrocytomas, seizures, cardiac rhabdomyomas, renal angiomyolipomas, polycystic kidney disease (contiguous gene deletion). May be mild course, seizures: infantile spasms, onset <2 y, or poor control has an increased risk of LD.
Renal US q1-3 y, + renal CT/MRI
TSC1– familial (30%), sporadic (15%)
TSC2– familial (50%), sporadic (60%-70%)
Renal Collagen IV-related nephropathies (Alport syndrome and thin basement membrane nephropathy)
XL AD AR
XL: COL4A5 AR/AD: COL4A3, COL4A4
Abnormal type IV collagen in the basement membrane of glomeruli
Ranges from isolated hematuria (thin basement) to progressive renal failure, cataracts, and deafness (Alport). ESRD: 90% by 40 y
Deafness: 90% SN deafness by 40 y
Nephrology follow-up, renal transplantation, management of deafness
Mutation analysis: COL4A5 (>80%)
Polycystic kidney disease
PKD1, PKD2, PKHD 1
ADPKD: abnormal polycystin complex resulting in altered calcium homeostasis
ADPKD: bilateral renal cysts, cysts in the liver, seminal vesicles, pancreas, intracranial aneurysms, 50% renal replacement therapy by 60 y.
Nephrology follow-up, renal transplantation
Mutation analysis: PKD1 and PKD2 (>88%)
ARPKD: fetal/neonatal death, pulmonary hypoplasia from oligohydramnios, renal failure, hepatic fibrosis, 30%-50% mortality in peri/neonatal period.
NPHS1, NPHS2, WT1, LAMB2
Disruption of podocyte foot processes or slit membrane
Congenital nephrotic syndrome with renal failure. High mortality in first year of life. Infection risk high.
Periodic albumin infusions; diuretics; dialysis; transplant by 3 y; monitor for infection and treat aggressively
Detection rates not available.
Factor V Leiden
Slowed inactivation of factor 5 due to mutation at APC cleavage site -> increased thrombin. Homozygosity increases risk.
Venous thromboembolism. Risk increased by concurrent thrombophilic disorders. Pregnancy loss, DVT.
Warfarin or LMW heparin for recurrent venous thromboembolism.
Targeted mutation analysis (100%)
Reduced or absent factor VIII
Hemarthroses, intracranial bleeding, deep tissue hematomas; prolonged PTT
IV factor VIII prophylactically for severe disease and in trauma
Targeted mutation analysis– intron 22-A inversion (48%) Mutation analysis (43%)
Reduced or absent factor IX
Hemarthroses, intracranial bleeding, deep tissue hematomas; prolonged PTT
IV factor IX prophylactically for severe disease and in trauma
Mutation analysis (97%)
Sickle cell anemia
Glu6Val point mutation leads to distorted deoxygenated Hgb leading to a characteristic sickle shape of RBCs
Vaso-occlusive crises leading to pain crises, long bone pain, dactylitis, acute chest syndrome, priapism, stroke, MI. Long term: anemia, jaundice, cholelithiasis. NB: variable presentation with thalassemias
Acute episodes: hydration, pain control, antibiotics for acute chest syndrome. Long term: penicillin prophylaxis, hydroxyurea, transfusions
Targeted mutation analysis for Glu6Val. Frequency of mutation will differ based on ethnicity.
von Willebrand disease
Deficiency of von Willebrand factor: normally aids in platelet adherence for nl blood clotting
7 subtypes with bleeding, easy bruising, prolonged bleeding time, especially after surgery or tooth extraction; nl platelet count
Plasma-derived clotting factor concentrates, + desmopressin, fibrinolytic inhibitors, OCPs for menorrhagia.
Type 1 (most frequent): sequencing (60%-65%)
Decreased or absent alpha chains for Hgb formation
Hb Bart: loss of all 4 alpha chains
HbH: loss/dysfunction of 3 alpha chains
Alpha trait: loss/dysfunction of 2 alpha chains
Silent carrier: loss/dysfunction of 1 alpha chain
Hb Bart: hydrops fetalis, neonatal death
HbH: hemolytic anemia
Alpha trait: low MCV, low MCH
Silent carrier: none or mild anemia
Trait protective against malaria (aa/– or a-/a-) mild anemia, microcytosis)
aa/– more common in SE Asians than Africans (a-/a-)
Hb Bart: no Rx, recommend termination HbH: transfusion during hemolytic crises, + splenectomy, antibiotics
Targeted mutation analysis for common deletions, detection varies by population
Decreased or absent beta chains for Hgb formation
β0–when no HbA present
β+–if some HbA present
Thalassemia major: severe microcytic anemia and hepatosplenomegaly in first 2 years of life, crew cut skull on x-ray
Thalassemia minor: milder anemia that only rarely requires treatment with blood transfusion
Thalassemia major: transfusions with chelation
Targeted mutation analysis detection varies by population. Sequencing (99%)
242300 308100 146800 604777
TGM1, ALOXE3, ALOX12B, ICHTHYIN, ABCA12, and CYP4F22
Multiple mechanisms involved in maintenance of cornified layer of the epidermis
A continuum of thick scaly skin that may range from severe with restriction of movement to milder forms. Harlequin ichthyosis (severe and often fatal form), lamellar ichthyosis (LI), and nonbullous congenital ichthyosiform erythroderma (NCIE).
Treatment of infections, petrolatumbased creams/ointments, + alpha-hydroxy acid or urea preparations to promote peeling and thinning of the stratum corneum
Mutation analysis: TGM1 (90% LI) ALOX12B (6%) ALOXE3 (4%) ABCA12 (1-2% LI, >93% HI) ICHTHYIN (1%- 2% negative for TGM1)
Lack of NF-κB leads to apoptosis in cells
Major: skin changes: erythema > blister > hyperpigmented streaks > atrophic skin patches
Minor: hypo/andontia, alopecia, wooly hair, nail pitting, retinal neovascularization. Male fetuses miscarry
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