hypotonia (poor muscle tone), poor moro reflex, upward slanting palpebral fissures, small/abnormal ears, hypereflexible joints, hip dysplasia, short curved dyspasia 5th finger (clinodactyly), transverse (single) palmar crease, excess skin on back of neck (nuchal fold), round flat face with increased distance between the eyes.
females may menstruate, may be fertile, often have ovulatory dysfunction resulting in cycle abnormalities, and pose a contraceptive dilemma
males generally have low fertility potential, likely secondary to low serum testosterone levels
congenital heart defects cause for early death.
increased risk for acute lymphoblastic leukemia
before birth: excess amniotic fluid (polyhydramnios), pre/postnatal growth retardation, decreased fetal activity and a single umbilical artery
at birth: increased muscle tone (hypertonia), small head size (microcephaly, low-set malformed ears, a small jaw (micrognathia), cleft lip and/or palate, clenched fist with the index finger and little finger overlapping the 3rd and 4th fingers, small (hypoplastic) nails of hands and feet, rocker-bottom feet, shortened (hypoplastic) sternum with missing 12th ribs, inguinal or umbilical hernia, Meckel's diverticulum, omphalocele, malrotation of the bowel, horseshoe kidney, diaphragmatic hernia and cardiac defects
nondisjunctional event that occurs in greater frequency with advancing maternal age. translocations rare
midfacial and forebrain development (holoprosencephaly), intrauterine growth retardation, micrognathia with cleft lip and/or palate, small eyes (microphthalmia) and colobomas, extra digits (polydactyly) and fused digits (syndactyly), low-set ears, broad flat nose, scalp defect, single umbilical artery, microcephaly, cardiac defects are prevalent, especially defects of the septal wall. common renal anomalies include polycystic kidney, hydronephrosis, horseshoe kidney, and duplication of the ureters. severe intellectual disability.
nondisjunctional event that occurs in greater frequency with advancing maternal age. translocations rare.
velopharyngeal incompetence; VPI, cleft palate/speech and feeding problems, cardiac defects, facial appearance (asymmetric crying facies, overfolded ears, small, recessed jaw, bulbous nasal tip, long face). learning problems, hypocalcemia, immunodeficiency due to absent or small thymus gland. multidisciplinary evaluation involving healthcare providers from many specialties is often necessary.
in the neonatal period, measure serum calcium concentration and absolute lymphocyte count and perform a renal ultrasound and an ultrasound of the heart
decreased birth weight, short stature, gonadal dysgenesis, transient congenital lymphedema (causes puffy hands/feet, webbed neck), thyroid disease, dysmorphology (cystic hygroma>webbed neck>low-posterior hair line, strabismus, high arched palate, cubitus vulgus (abnormal outward bending of the elbow), cardiac anomalies (coarctation of aorta), hearing loss, ovarian degeneration (estrogen replacement therapy is indicated, with resulting menstruation). pregnancy only possible using artificial reproductive technologies. 45X/46XY mosaicism, increased risk of gonadoblastoma. mental retardation NOT a feature but delays in visual-spatial organization and math more frequent. paternal sex chromosome is most likely to be missing. no association between occurrence and advanced maternal age. usually sporadic with little increased recurrence risk. environmental causes (teratogenesis) (e.g. congenital rubella infection, fetal alcohol syndrome, infant of diabetic mother)
ex. fetal alcohol syndrome. cardinal features: growth restriction, microcephaly, cognitive impairment, characteristic facial features (small head, epicanthal folds, flat midface, smooth philtrum, underdeveloped jaw, thin upper lip, short nose, small eye openings, low nasal bridge), and documented alcohol exposure.
ex. congenital rubella syndrome (microcephaly, heart disease, petechiae and purpura, eye anomalies may include cataracts, glaucoma, strabismus, nystagmus, microphthalmia, and iris dyslpasia)
multiple cafe au lait spots
axillary and inguinal freckling
multiple cutaneous neurofibromas
iris Lisch nodules
learning disabilities (~50%)
less common but potentially more serious manifestations include plexiform neurofibromas, optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy
VARIABLE EXPRESSIVITY. most likely results from a combination of genetic, nongenetic, and random factors
in some of the tumors, both a mutation in the normal allele and the germline mutation are seen - leading to cell proliferation
modifier genes may also play into the variability
deletion of the whole NF1 gene is associated with large numbers and early appearance of cutaneous neurofibromas, more frequent and more severe cognitive abnormalities than average, and sometimes somatic overgrowth, large hands and feet, and dysmorphic facial features
NF1, chromosome 17, >500 mutations identified including missense, nonsense, insertions, deletions, and others, presumed to be loss of function mutation
protein = neurofibromin whose function is not fully understood. may act as a tumor suppressor
abnormal protein is truncated and rendered non-functional
the NF1 gene product, neurofibromin, functions in part as a negative regulator of the RAS proto-oncogene by accelerating the conversion of active GTP-bound RAS to its inactive GDP-bound form. Active RAS, as a result of reduced or absent neurofibromin expression, leads to increase cell growth and facilitates tumor formation.
connective tissue abnormality affecting multiple systems (pleiotropy) with clinical variability (variable expressivity), but with 100% penetrance
ocular - myopia, ectopic lentis (lens dislocation), retinal detachment, glaucoma
skeletal - bone overgrowth and joint laxity, arachnodactyly (long fingers), dolichostenomelia (extremities long for size of trunk), pectus excavatum (overgrowth of ribs force chest inward; concave) or pectus carinatum (force chest outward; convex), scoliosis
cardiovascular - aortic root enlargement, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery
if managed properly, life expectancy can be normal
ocular: ophthalmologist, glasses, lens dislocation may require surgery, annual exams
skeletal: orthopedist, scoliosis
cardiac: cardiologist. evaluate with ECG for aortic root dilation. beta-blockers reduce hemodynamic stress on the aortic wall. losartan, a common blood pressure drug, is showing promise in the prevention of aortic root dilatation
avoidance: contact sports, competitive sports, activities causing joint injury, decongestants and caffeine (stimulate cardiovascular system), LASIK surgery