(Pediatrics 1998;1C2:e69; Urea Cyclc Disorders.Vadem écum Metabolicum; 2004:25)
• Serum and plasma: C e ntrifug e several ccs im m ediately and sto re frozen
• D rie d b lo o d s p o t on filte r paper card
• U riñe : Freeze Im m ediately
• Bile: S pot on filte r paper and sto re , if available
• 3 -1 0 cc EDTA w h o le b lo o d fo r D N A analysis
• Skin bx: Up to 24 h r postm ortem . stored at ro o m tem p o r 37cC in tissue cx med o r sterile saline
• C o n sid e r CSF and v itre o u s fluid; b oth should be frozen
• A u to p sy is encouraged
T RI SO M Y 13
D e f in i ti o n (A m J Med G enet A 2006:140:1749: Nclson Texibook o f Pediatrics, 17th ed.)
• Patau syndrom e
• 0.85:10,000 live b irth s, large percentage term ln a te d before b irth
• Death fre q u e n tly in I s t m o o f life
• Clinical m anifestations: C le ft lip, polydactyly, lo w -se t ears, holoprosencephaly, m lcrophchalm ia, cardiac defects, absent ribs, visceral and genital anomalies
T RI SO M Y 18
D e f in i ti o n (A m J Med G enet A 2006:140:1749; Neison T extbook o f Pediatrics. 17th ed.)
• Edwards syndrom e
• 1.29:10,000 live b irth s, large percentage te rm ln a te d befo re b irth
• D eath fre qu e ntly in 1 st m o o f life, 5% survival to 1 st birthday
• Clinical findings: Closed fists w / índex fin ge r overlapping 3 rd digit and 5th d ig it over- lapplng 4 th digit, ro c k e r-b o tto m feet, microcephaly, m icrognathia, cardiac/renal m alform
T R IS O M Y 21
D e f in itio n (Lancel. 2003:361:1281: A m Fam Physician 1999:59:381)
• D o w n ’s syndrom e; m o st com m o n genetic syndrom e. 1 :8 0 0-1,0 00 live b irth s
• Congenital h e a rt disease, myelodysplasia in n ew b o rn and duodenal atresia highly specific fo rT ris o m y 2 1
• 95% 2/2 non disju nctio n (nonsegregation) c h ro m o 21 in o ocyte o r sp erm atocyte
• 4 -5 % caused by tra nsloca tion o f one ch ro m oso m e 21 to a n o th e r
• 1% o f cases are mosaics (n o nd isju nctio n o ccu rrin g a fte r co nce ptio n ) D ia g n o s is
• A t b irth : C o nste lla tio n o f features and c o n firm a tio n by karyo typ e
• Prenatal: Quad screen: M aternal a -fe to p ro te in & E striol lo w e r than nml and ¡5-HCG
& Inhibin A higher (7 0 -84 % sensitivity)
• Fetal US w / nuchal translucency, s h o rt fem urs, cardiac anomalies, and duodenal atresia
• W om en >35 yo w/increased risk. C h o rio n ic villus sampling can be done b tw 9 and 11 w k gestation, amnio b tw 16 and 18 w k. Fecal cells examined fo r chrom osom al abn
• Physical actributes: H yp oto nia. fíat face, upward/slanted palpebral fissures, epicanthic folds, Brushfield spots, mental re tarda tion . cardiac m a lform ations. simian crease C o m p lic a t io n s
• C ongenital h e a rt disease: 40-60 % o f infants -4 ECG and TTE
• C o m p le te A V canal defects (60% o f h e a rt defects);VSD (32% );TOF (6%)
• Gl defects: Esophageal atresia,TEF, p yloric stenosis, duodenal atresia, Meckel, H irschsprung, ¡m pe rfo rate anus, and GERD; 5 -1 5 % w / Celiac dz
• ENT: Midfacial m alform ations in terfe re w ith nm l drainage o f Eustachian tube and sinuses
• R e curre nt o titis media, sinusitis, and pharyngitis
• O rth o p e d ic:
• A tla n to -o ccip ita l instability, hyperflexibility, scoliosis
• Atlancoaxial instability: 13% asymp & need m o n itoring . N o c o n ta ct sp orts
• Late hip dislocation (>2 yo),SC FE,patellar subluxation o r d is lo c a tio n .fo o t d efo rm itie s
• T h yro id dz fo llo w e d by yearly TSH. G H def and gonadal dysfunction may also be present
• 'C ongenital cacaracts and o th e r eye disease
• Transient m ye lo prolife ra tive d is o rd e r (leukem oid re action) in 10% o f n ew b o rn s (rare in n o n -D o w n ’s infants). Increased risk o f A LL
• Seizure d is o rd e r in 5 -1 0%
• D ental problem s and feeding difficulties
• Refer fo r early in te rve n tio n to help w ith developm ent
T U R N E R SYNDROME
D e f in itio n (A m Fam Pnysidan 2007:76:405: Clin Pediatr (Phiia) 2006:45:301)
• Partial o r co m p lete absence o f X ch ro m oso m e , 45 X karyo typ e
• 50 per 100,000 live female b irth s
D ia g n o s is (N a l Cl n Pract Endocrinol M etab 2005:1:41)
• C o nside r ¡n girls w ith s h o rt stature (2 SD b elo w mean height fo r age), p rim a ry am enorrhea. lack o f brease developm ent, delayed p u b e rty
4 C o nside r in fetus w / hydrops, T nuchal translucency, cystic hygroma, o r lymphedema 4 D x made w ith ka ryo typ in g -4 chrom osom al analysis o f 30 p eripheral lym phocytes 4 50% w / missing X ch ro m oso m e in all cells studied, o th e rs w / 45, X /4 6 , X X mosaic C lin ic a l M a n ife s ta tio n s
4 Risk o f congenital h ea rt defects -» 75% w ith e ith e r co arcta tio n o f the a orta o r bicuspid a o rtic valve. Risk o f progressive a o rtic r o o t d ila tion o r dissection
4 Risk o f cong lym phedema, renal m a lform , hearing loss, oste o po ro sis, obesity, and diabetes
4 N o rm a l IQ , although may have d ifficulty w / nonverbal, social, and p s ych o m o to r skills 4 Physical exam: Misshapen o r ro ta te d ears, lo w p o s te rio r hairline, w ebbed neck, broad
chcst w ith w id e ly spaced nipples and cubitus valgus, sh orte n ed 4 th metacarpal 4 A lm o s t all are in fe rtiie
M a n a g e m e n t (E n do crh e 2011 PMID 22147393)
Treat s h o rt statu re w ith G H therapy throu g h bone age o f 14 yo.
• Estrogen in adolescence fo r pubertal developm ent and prevention o f o steoporosis w ith Ca + V it D. C o ntin u é th ro u g h o u t life
4 Hearing tests, p ed ia tric o p th o fo r hyperopia and strabismus, regular dental visits 4 Echocardiogram to río congenital h e a rt defects, 4 e x t BPs to fo llo w fo r co arcta tio n
• Renal u ltrasound f o r renal m alform ations
• >4 yo r /o celiac w ith tissue transglutaminase im m unoglobulin A & r p t q2—4yr
C lin ic a l M a n ife s ta tio n s
• V om iting and lethargy a fte r fasting ¡n a 3 -1 5 m o child
• M ost dlagnosed <4 yo, undiagnosed m o rta lity = 2 0-25 %
• H yp oke totlc hypoglycemia provoked by fasting (do n o t present in nonfasting condltions) -» may develop coma (fro m hypoglycemia + to x ic ity o f fatty acids and metabolites)
• Muscle weakness w orsens w ith increased delay in diagnosis Diagnosis
• D e te cte d on NBS
• C o n firm dx w ith plasma acylcarnltine analysis and u rin a ry organic acids
• May need skin bx fo r enzyme eval o f fibroblasts to n a rro w dow n actual enzym atic defect M a n a g e m e n t
• A vo id fasting o r decreased d ieta ry fat intake
• S upplem ent w ith L-ca rnitine (especially during illnesses)
• Tre a t aggressively even d uring m ild illnesses w ith IV glucose and ca rn ltlne
POSTMORTEM LABS
(Pediatrics 1998:1 C2:eó9; Urea Cyclc D isorders,Vademécum Meiabolicum ; 2004:25)
• Serum and plasma: C entrifug e several ccs im m ediately and store frozen
• D rie d b lo o d s p o t on filte r paper card
• U riñe : Freeze im m ediately
• Bile: S pot on filte r paper and store, if available
• 3 -1 0 cc E DTA w h o le b lo o d fo r D N A analysis
• Skin bx: Up t o 24 h r postm ortem , stored at room tem p o r 3 7 'C in tissue cx med o r sterile saline
• C o n sid e r CSF and vitre o u s fluid; b oth should be frozen ' A u to p s y is encouraged
T RI SO M Y 13
D e fin itio n (A m J Med G c n c t A 2006:140:1749: Nelson T cx A o o k c f Pediatrics, 17th ed.)
• Patau syndrom e
• 0.85:10,000 live b irth s, large percentage te rm in a te d before b irth
• Death fre q u e n tly in 1 st m o o f life
• Clinical m anifestations: C le ft lip, polydactyly, io w -se t ears, holoprosencephaly, m icrophthalm ia, cardiac defects, absent ribs, visceral and genital anomalies
T RI SO M Y 18
D e fin itio n ( A n j Med G enet A 2006:140:1749; N elson Te xib oo k o f Pediatrics. 17th ed.)
• Edwards syndrom e
• 1.29:10,000 live birth s, large percentage te rm in a te d before b irth
• D eath fre q u e n tly ¡n 1st m o o f life, 5% survival to 1 st b irth da y
• Clinical findings: Closed fists w / Index finger overlapping 3rd digit and 5 th d ig it over- lapping 4 th digit, ro cker-botcom feet, microcephaly, m icrognathla, cardlac/renal m alform
T RI SO M Y 21
D e fin itio n (Lance! 2003:361:1281; A m Fam Physician 1999:59:381)
• D o w n ’s syndrom e; m o st com m o n genetic syndrom e. 1 :8 0 0-1,0 00 live b irth s
• Congenital h ea rt disease, myelodysplasia in n ew b o rn and duodenal atresia highly specific fo r Trlsom y 21
• 95% 2/2 n on disjunction (nonsegregation) c h ro m o 21 ¡n o ocyte o r sperm atocyte
• 4 -5 % caused by tra nsloca tion o f one ch ro m oso m e 21 to a n o th e r
• 1% o f cases are mosaics (n o ndisjunction o ccu rrln g a fte r co nce ptio n ) D iagnosis
• A t b irth : Constellacion o f features and co n firm a tio n by ka ryo typ e
" Prenatal: Q uad screen: M aternal a -fe to p ro te in & E striol lo w e r than nm l and (3-HCG
& Inhibin A higher (7 0 -84 % sensitivity)
• Fetal US w / nuchal translucency, s h o rt fem urs, cardiac anomalies, and duodenal acresia
• W o m e n >35 yo w/increased risk. C h o rio n ic villus sampling can be done b tw 9 and 11 w k gestation. amnio b tw 16 and 18 w k. Fetal cells examined fo r chrom osom al abn
• Physical a ttrib u te s: H yp oto nia, fíat face, upward/slanted palpebral fissures, e picanthic folds, Brushfield spots, mental re tarda tion , cardiac m a lfo rm a tion s, simian croase C o m p lic a tio n s
• Congenital h e a rt disease: 4 0-60 % o f infants h> ECG and TTE
• C o m p le te AV canal defects (60% o f h e a rt defects);VSD (32% );TOF (6%)
• Gl defects: Esophageal atresia,TEF, p yloric stenosis, duodenal atresia, Meckel, H irschsprung, im p e rfo ra te anus, and GERD; 5 -1 5 % w / Celiac dz
• ENT: Midfacial m a lform ations in te rfe re w ith nml drainage o f Eustachian tube and sinuses
• R e cu rre n t o titis media, sinusitis, and pharyngitis
• O rth o p e d ic:
• A tla n to -o c c ip ita l instability, h yperflexibility, scoliosis
• A tlan toa xia l instability: 13% asymp & need m o n ito rin g . N o c o n ta ct sports
• Late hip dislocation (>2 yo),SC FE,patellar subluxation o r d is lo c a tio n .fo o t d efo rm itie s
• T h yro id dz fo llo w e d by yearly TSH. G H d ef and gonadal dysfunction may also be present
• Congenital cataracts and o th e r eye disease
• Transient m ye lo prolife ra tive d is o rd e r (leukem oid re a ction ) in 10% o f n ew borns (rare in n o n -D o w n 's infants). Increased risk o f A L L
' Seizure d is o rd e r in 5 -1 0%
• Dental p roblem s and feeding difficulties
• Refer fo r early in te rv e n tio n to help w ith developm ent
T U R N E R SYNDROME
D e f in i ti o n (A m Fam Physician 2007:76:405; Clin Pediatr (Phila) 2006:45:301}
• Partial o r co m p lete absence o f X ch ro m oso m e , 45 X karyo typ e
• 50 p er 100,000 live female b irth s
Diagnosis (N a t Clin Pract E ndocnnol Metab 2006:1:41}
• C o n sid e r in girls w ith s h o rt statu re (2 SD b elo w mean height fo r age), p rim a ry am enorrhea, lack o f breast developm ent, delayed p u b e rty
• C o nside r in fetus w / hydrops, T nuchal translucency, cystic hygroma, o r lymphedema
• D x made w ith ka ryo typ in g -> chrom osom al analysis o f 30 p eripheral lym phocytes
• 50% w / mlssing X ch ro m oso m e in all cells studled, o th e rs w / 4 5 .X /4 6 , X X mosaic C lin ic a l M a n ife s ta tio n s
• Risk o f congenital h ea rt defects -> 7 5 % w ith e ith e r co arcta tio n o f the a orta o r bicuspid a o rtic valve. Risk o f progressive a o rtic ro o t d ila tion o r dissection
• Risk o f cong lymphedema, renal m a lform , hearing loss, oste o po ro sis, obesity, and diabetes
• N o rm a l IQ , although may have d ifficu lty w / nonverbal. social, and p sych o m o to r skills
• Physical exam: Misshapen o r ro ta te d ears, lo w p o s te rio r hairline, w ebbed neck, broad chest w ith w id e ly spaced nipples and cubitus valgus, sh orte n ed 4 th metacarpal
• A lm o s t all are in fe rtile
Management (Endocrine 2011 PMID 22147393}
Treat s h o rt statu re w ith G H therapy throu g h bone age o f 14 yo.
• Estrogen in adolescence f o r pubertal developm ent and prevención o f osteoporosis w ith Ca + V it D. C o ntin u é th ro u g h o u t life
• Hearing tests, p ed ia tric o p th o fo r hyperopia and strabismus, regular dental visics
• Echocardiogram to r /o congenital h e a rt defects, 4 e x t BPs to fo llo w fo r co arcta tio n
• Renal u ltrasound fo r renal m a lform ations
• >4 yo r/o celiac w ith tissue transglutaminase im m unoglobulin A & r p t q 2 -4 y r
• Annual TFTs, LFTs, fasting lipids, and glucose
• If Y ch ro m oso m e ¡s present, 12% ris k o f gonadoblastom a; m ust re fe r fo r rem oval C o m p lic a tio n s
Scrabismus, hearing loss, re cu rre nt o titis media, to o th anomalies, renal malform, autoim mune thyroiditis, celiac dz. congenital hlp dysphsia, and scollosis, T risk colon, breast, and endom etrial Ca (from estrogen use), A o rtic dissection o r rupcure especially w / pregnancy.
F R A G I L E X
D e f in i ti o n (C u rr Ger.omlcs 2011:12:216; Clin Pediatr (Phiia) 2005:44:3/1)
• X -lin ke d dom ina n t w / J. penetrance. 2/2 abn co m p iem en t o f trln u c le o tid e repeats
« Full m u tatio n usually w / phenotype. Mosaicism com m o n
• Full m utation has >200 C G G repeats -> absence o f FMR-1 protein, which ¡s responslble fo r the symptom s.The greater the repeats, the m ore severe the disease
• O ccurs in b oth males and females
• M o st co m m o n Inh e rite d cause o f mental re tarda tion
• Prevalence rate o f 1:4,000 males, 1 :8,000-9,000 females D ia g n o s is
• Classic triad: M acro -o rch idism , large o r p ro m in e n t ears, and a long n a rro w face
• Suspect dx in any infant o r to d d le r w / developm ental delays (esp speech) o r maternal FHx o f MR, developm ental disabillties o r learning dlsabilitles
• Males w / full m u tatio n : Global dev delays and MR, may have autistic spectrum d iso rd e r
• Physical exam: L o o k fo r macrocephaly, p ro m in e n t forehead, hyperextensible joints, stre tch y skin, MVP, and large testlcles
• Females w /full m u tatio n -> m ildly affected w ith n orm al developm ent to MR
• FA4R- 1 gene ¡s located on X ch ro m oso m e M e d ic a l C o m p lic a t io n s
• Have n orm al life expectancy; re ce n t studies d em ón strate stat sign increase in rate o f o besity (31% com pared co 18% in age-matched Controls; associated w I P ra d e r-W illi phenotype)
• R e cu rre n t o titis media and sinusitis
• MVP develops in adolescence o r adu ltho o d
• H yp o to n ia is co m m o n. may have seizures
• M acro -o rch idism
• <í s tend to e xhib ir social avoidance. May have A D H D ; benefic fro m early in te rv e n tlo n
K L I N E F E L T E R
D e fin itio n (A m Farm Physcian 2005:72:2259)
• Usually 47, X X Y ka ryotype. Can include e xtra X ch ro m oso m cs o r Y chrom osom es
• N o nd isju n ctio n during m eiosis w ith orig in fro m e ith e r parent
• 1:1,000 boys; mosaicism in 15% o f men D ia g n o s is (In iJ Endocrino! 2012: PMID 22291701)
• Males present w / in fe rtility o r gynecom astia as teens o r adults
• 50% <18 yo w / m ild neurodevelopm ental d isorders
• Late o r ¡ncom plete p u b e rty should p ro m p t a w o rk u p
• FSH and LH nm l in p re -pu b erta l pts, then high fro m m id -p u b e rty w I lo w testo stero n e
• K aryotyp e to c o u n t sex ch rom osom es in 50 cells (¡n case o f mosaicism) C lin ic a l M a n ife s ta tio n s
• A lm osc all men are in fe rtile (3% o f all male In fe rtility )
• Testosterone def, small testes,-L facial hair, gynecomastia, I pubic hair, and small penis
• Tall and slender w ith long legs and s h o rt to rs o
• May develop o ste o po ro sls M a n a g e m e n t
• N e urod e velo p m e nta l evaluación a t diagnosis
• H o rm o n e therapy fo r lo w testo ste ro n e levels o r if h ypergonadotropism is present
• Gynecom astia predisposes men to breast cáncer; frequeney 20—50xs > in norm al men
LysosomalDz11-9
V A C T E R L
D e fin itio n {O rp h a n e l J Rare D i: 2011;6:56;j Med G cne t 2006:43:545)
• Association o f 3 o f the follow ing: V ertebral defects, anal atresia cardiac defects, tracheo- esophageal fístula, renal m alform ations and lim b defects; incidence 1:10,000-1:40,000, T risk in infants o f m others w / D M
A s s e s s m e n t
• Infants w ith esophageal atresia o rT E F should be assessed fo r VACTERL
• H x o f teratogen exposure (especially m ethim azole), m aternal D M , FHx o f sim ilar issues
• TTE, lim b o r ve rteb ra l x-rays, renal u ltrasound, upp er & lo w e r Gl evals
• K aryotyp e fo r exclusión o fT ris o m y 1 8 ,2 1 , FISH fo r 2 2 q 1 1 d e le tio n .A rra y -C G H if karyo typ e and FISH studies are nm¡ to assess fo r chrom osom al abnorm ality.
• M ulcidisciplinary managem ent f o r abnorm alities